Sometime in the 2050's, crop blight has caused civilization to regress into a failing agrarian society, much like the Great Depression of the 1930's. Many staple crops of United States agriculture have failed within the past few years, to include wheat and okra, and the only crop remaining is corn, however, it is not expected to last much longer. The military does not exist anymore and trends are a thing of the past with survival being mankind's main priority. Automobiles have not been produced since the 2010's and have to be kept in running condition. The majority of cities in the United States are almost abandoned with most of the population now living in rural areas eking out a living as farmers. Corn now makes up the main staple to people's diets, as most other foods can no longer be grown. Elderly people that look like survivors from the Great Depression of the 20th century are giving interviews about all the dust storms and having lived in this world, to include the daughter of the main character.
Former NASA test pilot Cooper runs an Eastern Colorado farm with his father-in-law, his teenage son, and 10-year-old daughter, Murphy. His father-in-law Donald laments on the good old days when he was a kid: how technology was constantly changing and gadgets being invented and the Earth once having six billion people. His son Tom is an average student in high school whom the administrators want to be a farmer instead of an engineer. And his daughter Murph is a feisty pre-teen destined for a future as a scientist. The Cooper family live a generally simple life with attendance at a baseball game a rare treat.
Murphy believes her room is haunted by a ghost trying to communicate with her. She and Cooper discover the "ghost" is an unknown intelligence sending coded messages using gravitational waves, leaving binary coordinates in the dust that direct them to a secret NASA installation led by Professor John Brand. Brand reveals that a wormhole was discovered 48 years ago, but never revealed to the public, and possibly created by an alien intelligence that leads to new planets that may offer hope for survival. NASA's "Lazarus missions" have identified three potentially habitable worlds orbiting the black hole Gargantua: Miller, Edmunds, and Mann, named after the astronauts who surveyed them. The staff questions Cooper as to how he was able to find the top secret NASA bunker and refuse to believe his story. But nevertheless, Brand recruits Cooper to pilot the spacecraft Endurance to recover the astronauts' data; if one of the planets is habitable, humanity will follow on space stations. Cooper's departure devastates Murphy, and they part on bad terms.
On Endurance, Cooper joins Brand's daughter, biologist Amelia; scientists Romilly and Doyle; and robots TARS and CASE. They begin a two-year hibernation to Saturn. After awakening near Saturn, Cooper watches a video of Tom and Donald with them explaining Murph is still mad at Cooper leaving. They enter the wormhole and head to Miller, but discover the planet is so close to Gargantua that it experiences severe gravitational time dilation: each hour on the surface is seven years on Earth. They descend to the planet, which proves inhospitable as it is covered by a shallow ocean roiled by enormous tidal waves. As Amelia attempts to recover Miller's data, a wave hits, killing Doyle and delaying the shuttle's departure. When Cooper and Amelia return to Endurance, 23 years have passed.
Devastated by the time that has passed, Cooper reviews all the videos from back home. The first video has his son Tom telling him how he finished second in his class, met a nice girl thinking she is the one for him to marry. The next video is with Tom showing Cooper his granddaughter Jessie. The next video is with Tom telling Cooper that Donald had died and is buried next to Jessie, who also died earlier and Tom reconciling the fact that Cooper is probably gone and that he hopes he is at peace. Finally, an apparent live recording comes from his daughter Murph, her first recording since she and her father separated on bad terms 25 years ago. She tells him she's learned to accept his disappearance and that today is her birthday and that she is now the same age as her father when he left and even more upset because he told her they might be the same age when he returns.
On Earth, the adult Murphy is now a NASA scientist assisting Brand with the equation that will enable NASA to launch its massive space stations via gravity. On his deathbed, Brand admits he already solved the problem and determined the project is impossible; he covered up his findings and put his faith in a "Plan B": using fertilized embryos to start humanity anew. However, Murphy concludes that Brand's equation could work with additional data from a black hole's singularity.
Low on fuel, Endurance can only visit one more planet before returning to Earth. Amelia suggests that next destination be Edmunds but Cooper disagrees on the basis that this might be an emotional decision for Amelia as she loves Edmunds. In this conversation Amelia suggests love as a demonstration of force from higher dimension however no one agrees with her. The team finally selects Mann's planet, as Mann is still transmitting. However, they find it to be icy and inhospitable and after their arrival and awakening of Mann himself, he reveals he always knew Plan B was the mission's true goal, and faked data about his planet's viability so Endurance would rescue him. Mann breaks Cooper's spacesuit visor and leaves him to die, and flees to Endurance on a shuttle; Romilly is killed by a bomb Mann set to protect his secret. Amelia rescues Cooper on the other shuttle, and they arrive at Endurance in time to witness Mann docking improperly. The airlock explodes, killing Mann and causing serious damage, but Cooper uses the shuttle to get Endurance under control.
Back on Earth, Murphy and fellow coworker and physician Getty make a trip to the Cooper farm to examine Tom's son Coop. Getty is determined to get the entire family away from the farm from dust contamination to safety, but Tom is infuriated and makes them leave. Murph knows in her subconscious that the ghost in her bedroom is still trying to communicate to her. She turns back to the farm and sets the cornfields on fire to distract Tom and goes back into the farmhouse bedroom trying to make sense.
Nearly out of fuel, Cooper and Amelia plan to slingshot Endurance around Gargantua on a course toward Edmunds. TARS and Cooper detach into the black hole, sacrificing themselves to collect data on the singularity and to propel Amelia by dropping the ship's mass. They emerge in an extra-dimensional "tesseract", where time appears as a spatial dimension and portals show glimpses of Murphy's childhood bedroom at various times. Cooper realizes the alien beings may be future humans and have constructed this space so he can communicate with Murphy and save humanity. It turns out all along that Cooper himself was the ghost in Murph's bedroom trying to communicate with her, pushing books off her shelves and leaving the binary pattern in the dust on her floor. Using gravitational waves, Cooper encodes TARS' data on the singularity into the adult Murphy's watch, allowing her to solve Brand's equation and evacuate Earth. Murph receives the data on the watch just minutes before Tom comes back from the crop fire and assures him that it was her father trying to save them. Tom is befuddled by all this, but accepts her hug. The beings then close the "tesseract", with Cooper assuming all went well and he is ejected from Gargantua back into the Solar System near Saturn.
Due to the time dilation from the entire mission, an additional 64 years passed when Cooper was ejected from Gargantua. Cooper wakes up in a hospital bed by a doctor and told to take it slow since he is now "124 years old", even though he hasn't aged. He looks outside at a baseball game then up at a non-existent sky, but upside down houses. He's revealed to be on Cooper Station near Saturn, which he thinks is named after him but learns is actually named after his daughter. Humans have evolved to become an advanced spacefaring race at this point -- a space police vehicle had found Cooper near Saturn right before his oxygen exhausted. He is shown the old farmhouse he and his family lived in, which is now a museum exhibit. There are videos of elderly people being interviewed all over the museum, which were shown at the beginning of the movie. Cooper also finds a shorted out TARS and repairs the robot. They are both on the front porch that "night" with Cooper drinking beer like he and Donald used to, but he's dissatisfied with pretending to be home and looking around at the artificial surroundings.
After an 89 year absence from her father and having been in cryosleep for two years, a dying Murph, who has led humanity's exodus and surrounded by her children, grandchildren, and great-grandchildren, reunites with her father. She made peace with his absence long ago and knows he was the ghost who sent her the messages, but doesn't want him to stay and see her die. Murphy advises Cooper and TARS to search for Amelia, who has begun preparation on Edmunds' planet. While Amelia waits on Edmunds, Cooper steals another ship and sets out to find her.