The movie opens in a similar fashion to the earlier films - a woman (played by Tanedra Howard, winner of the 'Scream Queens' reality show) awakens in a dark room with a trap on her head. The trap consists of a headset with two bolts placed at her temples in such a position that they will drill into her brain if activated. Across the room, separated from the girl's location by an impassable fence, an overweight man awakens with the same device on his head. Despite the girl's efforts to control the situation, the man panics, and accidentally activates the signature television message from Jigsaw. Jigsaw blames the two individuals for their roles in medical insurance 'crimes' (denying policies and claims for profit) and directs their attention to a scale mounted between the fences. One of the two will most certainly die, according to Jigsaw, and the survivor will be the one who cuts off the most flesh from their own bodies and places it on the scale in a 60 second time frame. To demonstrate what will happen if they are unsuccessful, Jigsaw gives a warning twist of the screw headsets, causing them minor injuries. When the tape stops, the man takes a knife from a table of tools left by Jigsaw and begins to cut away at his love handles for the scale. The girl is physically fit and has no such option, and first attempts to cut her chains. However, the man has already cut away a portion of his flesh and dropped it into the scale, and has started on a second. The girl panics and ties surgical tubing around her upper arm to form a makeshift tourniquet, and starts to cut her arm off with the knife. By the time she has done this, however, the man has placed a second hunk of flesh on the scale. With seconds left to spare, the girl grabs a butcher knife and brutally hacks away at her entire arm, severs it, and drops it into the scale. This swings the weight on her favor and the man dies as the headset drills into his brain. The girl survives, ending the opening scene.
The main protagonist is a man named William (Peter Outerbridge), a vice president of claims and investigations for a medical insurance company named "Umbrella Health". He supervises a team of six individuals who use a morally gray formula devised by William to determine when it would be appropriate to deny claims. His team, and William, are continuously portrayed as extremely nit-picky individuals when it comes to their work, actively seeking minor errors and faults in applications in order to cut down on costs rather then focusing on the lives of their clients. William himself is shown as being in council with the company's beautiful legal advisor, sharing a drink with her in his office as he is having a phone conversation with what sounds like a loved one. He says he is stuck in a meeting with legal and will be unable to attend a birthday. The legal advisor is helping William prepare a deposition, as he is coming under legal fire by a previous client, who died after William denied his insurance claims. In a flashback, it is demonstrated that the deceased was suffering from a heart condition, and William's team used an unrelated oral surgery from 30 years ago to justify their denials. William seems to see absolutely no problem with this, and commends his team as they continue to bring him similar issues.
Next, the successor to Jigsaw, Detective Hoffman, (Costas Mandylor), is shown in the glass box he had hidden away in at the end of Saw 5. The box transports him outside the 'crushing wall' trap area and into another room, where he simply exits the box and returns to double check the trap's success. He opens the walls and the corpse of Agent Peter Strahm is revealed to be a mangled and torn mess, confirming his death.
Detective Hoffman is called to the scene of the opening scene's trap some time in the future. Erickson, the FBI agent supervising Strahm from the previous movie, is already there with local authorities. They have discovered fingerprints at the scene of the crime, which is new to them. It turns out they belong to Agent Peter Strahm - Hoffman had retrieved Strahm's hand from the wall trap and is using it to further implicate him in traps as a cover for his own work. However, this is endangered when Erickson introduces their new partner in the investigation: Special Agent Lindsay Perez. She was Strahm's partner in the earlier films, who was assumed dead. It is explained that her death was only implied, as they didn't want to risk her life until they knew whom they could trust - as Strahm had been implicated as the Jigsaw Killer, and only Hoffman knew of his death, they decided it was safe to let Hoffman in on the secret. This alarms Hoffman a great deal, as she knew Strahm best, and is a threat to his cover.
Meanwhile, Jill Tuck, Jigsaw's wife from the previous films, is shown opening the Box from Saw 5. The contents are not fully disclosed at the beginning, but she does produce SIX envelopes, numbered 1-6, and a yellow envelope without a number. There are apparently other things in the box as well. She opens one of the envelopes, and inside is a picture of a young woman with glasses.
This woman is Pamela Jenkins, an investigative journalist who has published a book on Jigsaw. She corners Hoffman at a hospital in an attempt to get a statement from him, but Hoffman dismisses her as a sensationalist trying to profit from Jigsaw. Pamela offers her a deal - get her a lead on Jill Tuck's location (so she can interview her) and she will tone down the sensationalism. Hoffman says he'll see what he can do, and walks into the hospital room of the survivor from the opening scene's drill trap. She is missing her arm, but alive, and Hoffman begins to interrogate her about what happened, and whether or not she had learned anything from the game. The girl freaks out and starts yelling at Hoffman, distressed that losing her arm was supposed to teach her something.
Perez and Erickson present new evidence to Hoffman - Jigsaw pieces cut from the flesh of John Kramer's victims used a surgical blade, and "Strahm's" (Hoffman's) victims used a rough blade. There was only one victim who matched that, and that was Seth - the Pendulum Victim from Saw 5, which was Hoffman's first trap. This leads Perez and Erickson to start an investigation on Seth's trap and tape to see if they can find further evidence linking the new Jigsaw killings and the old one. Also, Strahm's fingerprints seem to contain high traces of Freon coolant chemicals, and they have yet to find out why (this is revealed later to be because Hoffman keeps the dead Strahm's hand frozen for use as misdirection via fingerprints). Hoffman keeps his calm, but is most certainly feeling the pressure - investigation of the tape and other clues will certainly implicate him, and not Strahm.
Jill goes to her clinic from the earlier films and is alarmed to see Hoffman there. She takes him into her office and they start discussing John (Tobin Bell, original Jigsaw). It is readily apparent that Jill is in on Hoffman's secret and they appear to be collaborating in some form regarding the Jigsaw killings and a new game. Hoffman claims they have to start the new game immediately, and demands the envelopes from Jigsaw's box. Jill agrees, and gives him not SIX envelopes, but FIVE. Hoffman is satisfied by this, and leaves, saying after this game, he never wants to see her again. Hoffman leaves, and Jill has a flashback to a time when John was alive, following his suicide and apparently after he has begun Jigsaw killings. He explains to Jill that addiction is not curable via treatment and that the only way to help people is 'his' way. He demonstrates this by bringing Amanda in - Amanda was a patient at the rehab clinic and was supposedly made 'clean' by John's game. Jill appears to be impressed.
Hoffman has a flashback of his own - he is helping adjust the crucifix trap from Saw 3 prior to its activation. It's victim, Timothy, is still unconscious in a wheelbarrow. Jigsaw arrives in wheelchair being pushed by Amanda. Jigsaw admonishes Hoffman for failing to use proper engineering knowledge (re: friction, grease, gear ratios) and tells him to check with him next time. Hoffman wonders if there will be a next time, and carelessly (and intentionally) dumps Timothy's body on the floor. Jigsaw is disturbed by his brutality, and Amanda warns Hoffman that he has not been tested. Hoffman says he does not need to be tested. Amanda counters that though Jigsaw may be dying, she isn't going anywhere. Hoffman threatens Amanda by saying she doesn't know that - he appears to be in on the fact that Amanda's test (re: keeping Lynn alive from Saw 3) is imminent. Jigsaw breaks up the tension by telling Amanda it is time to retrieve Dr. Lynn (Saw 3) from the hospital, and Amanda escorts Jigsaw out. On the way out, Jill is in the hallway waiting. Amanda seems hesitant, or embarrassed, and Jigsaw tells Amanda to go on ahead with her duties. Jigsaw is surprised that Jill showed up, and Jill begs Jigsaw to stop. Jigsaw promises Jill a way out even after he is gone, and gives her the key to the box she receives from his will, without explaining its purpose.
Back at William's office, it is now nighttime. He is watching a news broadcast about Jigsaw's killings continuing despite the death of Jigsaw. At this time, the power goes off in the building. William panics when he sees a shadowy figure moving across the office, and he retrieves his gun from his desk. William then hides under a desk, and ambushes the figure, shooting him. It is revealed to be a security guard, and as William tries to keep him alive, the guard tries to point out the actual Jigsaw pig-mask figure stalking behind them. William is then abducted by Jigsaw.
Also, the reporter, Pamela, is abducted by Jigsaw after following Hoffman's lead to Jill's apartment. She is in possession of a letter (the letter from Saw 3, written by Hoffman, to Amanda, though the contents are not revealed at this time). Jill says she doesn't know what it means, and Pamela is turned away. She leaves the letter for Jill anyway and is abducted by Jigsaw as she tries to leave the building.
William wakes up in a standing position, suspended by chains and held between two large blocks. Jigsaw explains that he is guilty of trying to decide who should live or die without regard for human life itself. Across from William is his janitor, who is strapped in an identical device. William has a bomb strapped to each of his limbs, controlled by separate keys. Only by proceeding through his tests within one hour will he receive the keys to release his limbs from the bombs. Jigsaw also says that if he fails to do so, he will never see his family again, implying they are in danger. To obtain the first key, he must survive his first test - after the tape ends, every breath that he takes will bring the stone blocks closer together, eventually crushing him. The only way to escape is to outlast the other individual in a 'hold-your-breath' contest. Despite William's best efforts to warn him, the janitor fails to hold his breath, and is crushed between the two blocks, releasing William. He uses a key in the room to release one of his wrists from the bomb-shackles and leaves via a ladder.
Meanwhile, a mother and son are trapped in a room with a vat of Hydrofluoric Acid linked to sprinklers, and a switch that says LIVE or DIE. They receive no tape or message, but can see the timer. In another similar room, Pamela is trapped with a tape. The contents are not revealed in their entirety, but it appears that they will die if William fails to accomplish his tasks.
William proceeds into a room where he must grab two handles. Upon doing so, it is revealed that his file clerk (a young healthy man with no family) and his secretary (a diabetic woman with a family) are being hung on suspended platforms. He must let go of one handle, and drop one of them to their deaths, or they both will die. This distresses William greatly, and it is apparent that the idea of murder and death is absolutely terrible for him. However, as the handles begin to build more resistance, he has no choice but to let go of one of them, and his hand slips - he 'chooses' to hold onto the handle saving the old woman, and the man falls and swings hard against the wall to his death. William apologizes that he has to continue, warns the woman to be careful, and takes the second key to free another arm.
On his way to his next test, William has flashbacks due to messages left under his shackles. The first is regarding a Party that he met John Kramer at. John and William discuss the similarities of their jobs - William chooses who lives or dies based on the formula he created for profitability. John admonishes him for not taking in to account the individual's desire to live. The next flashback regarding a final decision shows John at William's office, calmly stating that his insurance coverage denied him treatment - an experimental treatment using gene therapy could save his life. William denies him for it being unprofitable, and John is furious that William would allow him to die, calling him out on his lack of morality and the faults of the health care system, and telling him that if he thinks that he will not be judged by the living and dead, William will be proven wrong.
William then enters a room filled with steam. Below him, trapped in a maze, is his legal council from the beginning of the film. She has a device on her neck that will kill her unless she makes it through to the other side. She can only do this if William opens steam valves to allow her passage. Opening these valves, however, redirects the steam to harm William. He could merely pass and let her die, but wants to help her. He calms her down and guides her through the maze, taking blasts of steam to the face for her, and she gets through. However, there is no key to release her neck trap. Instead she is provided with a power saw, and an x-ray showing the key is inside a suture made on William's body. William says he will get it out for her (it appears the stitches are fresh and he could do so easily) but the woman panics and rushes her with the power saw. William tries to stop her, but she will not be stopped. He fights back long enough for her timer to spring and the trap on her neck penetrates her skull and kills her. William takes another key and frees his 3rd shackled limb.
At the site of the game, Hoffman is watching carefully from a viewing area, but is called away by the agents Erickson and Perez - they have found evidence based on the tape made by Hoffman at Seth Baxter's trap, and need him urgently. Hoffman leaves the site of the game and goes to investigate. When he arrives, he finds that they are about to break the distortion on the tape. Erickson and Perez begin to lay into Hoffman about the "Strahm is Jigsaw" theory, and begin to aggressively lay out evidence as the sound technician finishes up analysis on the data. As she comes up with Hoffman's voice, Hoffman cuts the power to the room and slashes Erickson across the throat and kills the sound technician. He corners Perez and stabs her repeatedly, demanding to know who else knows his secret. Perez defiantly says "Everyone" knows his secret, and dies. With so much evidence, Hoffman leaves Strahm prints using the frozen hand and douses the lab in gasoline, setting it ablaze. He then heads back towards the scene of the game.
William enters his last trap, trying to proceed with caution - he learns the next trap contains his entire investigative claims team. All six of them are strapped to a rotating carousel. A shotgun mounted to the carousel will kill them one by one unless William intervenes by pressing a button, which will stab him - however, he can only intervene twice. No matter what, four will die, and he has to choose. His team begins to quarrel amongst themselves, trying to justify why they should live or die. Despite himself not wanting anyone to die, he saves two women, and the rest are killed by the shotgun. He retrieves the final key and proceeds alone through the final hallway.
In the acid trapped cells, the mother and son start to panic - the timer is running out and they've yet to do anything. They decide to flip the switch, to the dismay of Pamela (she is able to view the entire game from her cell from a television provided by Jigsaw). However, the switch proves to do absolutely nothing. At this time, Jill arrives in the game's control area, but Hoffman is not there. She takes the remaining contents of the box and starts to put them in the room, placing the letter from Hoffman to Amanda on Hoffman's control desk. She hides, and Hoffman arrives. At this time the final seconds are counting down at the timer, and William arrives in the final door. He finds himself in a newly revealed chamber, between Pamela's acid cell and the family's acid cell. However, William appears to not recognize the family and instead turns to Pamela, who shares an emotional conversation - the family begins to yell at him for it being his fault. It is revealed that Pamela is in fact William's SISTER and is the family he was trying to save. The mother and son are the family of the man who died and William was facing legal action over. It is then revealed the true twist of the game - William had to make it there, with Pamela as the lure. The Jigsaw tape activates for the mother and son, telling them that he was sorry for mistreating them (they were not being tested but merely being held in the cell) and that they now have the option to kill William in front of his family just as William had denied their father/husband's claim and 'killed' him in front of them. Pamela and William beg for mercy and forgiveness, and the mother does not relent, going to the live/die switch (now active with William trapped) and saying this wasn't for revenge, but so that he could not 'kill' anyone else with his decisions. However, she cannot bring herself to flip the switch. The son, however, is far less squeamish and happily flips the switch. The switch activates a wall of needles that swing down into William's chamber, injecting him with the acid from the vats, dissolving him into a pile of bloody organs.
Meanwhile, Hoffman has arrived back at the scene of the game, in the control room, and sees the letter. He sits at his desk and reads it - the contents are revealed. Amanda had been at Jill's clinic with Cecil the night he robbed it, the night Jill had her miscarriage. The plot to rob the clinic was revealed to be at Amanda's design, and Hoffman knew. He threatened to reveal Amanda's involvement in the death of Jill and John's baby - a fact John neither was aware of, and the letter was blackmailing her to kill Dr. Lynn Denlon or the secret would be out. Amanda was unaware that her game was to keep Lynn ALIVE, however, therefore the game was sabotaged by Hoffman outside Jigsaw's knowledge by this blackmail - Hoffman wanted to be the last man standing and therefore avoid being tested. However, a shock is delivered through the chair and he falls unconscious. Jill reveals herself in the control chamber and straps Hoffman to it with leather traps, and reveals the final content of the box - the jaw splitter trap that Amanda had escaped from. Jill places it on Hoffman and leaves him for dead, to get revenge on him - Jill reveals that the sixth envelope was actually intended for Jill to use regarding a SIXTH target (the other five being the targets of William's game) - the sixth target was Hoffman. This is revealed to be the "test" Hoffman would not escape which was stated on Jigsaw's 'stomach' tape from the autopsy, and Jill, having been shown Hoffman's treachery by Pamela's letter, was now exacting Jigsaw's final will by 'testing' Hoffman. However, she left him with no means of escape (no key) to remove the headset.
Hoffman, now alone, breaks his hand by slamming the headset against his wrist and slips the broken hand through the leather restraint, and then uses the free hand to release himself from the chair. He tries to pry the headset off his head, but cannot. He then, at the last second, sends his head through a small window in a doorway, which catches the headset as it tries to crush his skull - it is now only partially open, but he is still trapped. Hoffman, out of immediate danger, then rips the side of his cheek through the metal bit in his mouth and forces his head out of the partially removed headset. He throws it down to the ground, screaming, having finally been 'tested' and lived.
After the credits, Amanda walks to a door hole and says, "Don't trust the one who saves you" twice to Jeff Denton's daughter. This may refer to Hoffman.