The film opens with a sequence designed to look like a classic video game, depicting Chev Chelios' (Jason Statham) fall from a helicopter during the final moments of the original Crank. Immediately after his fall, he is scooped off the street via snow shovel by group of Chinese medics and removed from the scene.
He wakes up in a makeshift hospital and sees doctors removing his heart while Johnny Vang (Art Hsu) watches. The doctors place Chev's heart in a red cooler with a padlock, and place a clear plastic artificial heart in his chest. Chev passes out.
Chev comes to some time later as an Asian woman is taking his temperature (rectally). Two doctors come in and talk about their plans to remove more of Chev's organs, including his penis. Chev beats up the doctors and stands up. He notices a yellow battery pack is attached to him, which he leaves on, and walks down the hall. The other rooms contain prostitutes, and he steals a set of clothes from one of the rooms without the occupants noticing. Outside, he gets in a gunfight and interrogates a thug in order to learn Johnny Vang's name and his location (Cypress Social Club), and then sets off to look for him.
On the road, Chev finds a phone in his pocket, and calls Doc Miles (Dwight Yoakam), who tells him that he has been fitted with an AbioCor Artificial heart. Once the external battery pack runs out, the internal battery will kick in and he will have one hour before it stops working. After the call, Chev asks a nearby driver where to find the Cypress Social Club, but crashes his car in the middle of the conversation, destroying his external battery pack. In order to keep going, Chev has the driver use his jumper cables on himself, and runs to the Cypress Social Club.
Upon arriving, Chev inadvertently saves a prostitute named Ria (Bai Ling) from an abusive, fat customer. Ria kills the customer and is immediately infatuated with Chev, claiming he Kevin Costner to her Whitney Houston (ala The Bodyguard). Vang escapes (still carrying the red, padlocked cooler) and Chev wants nothing to do with Ria, but she claims to know where Vang is. She takes Chev to Strip Please, where Chev is shocked to find into his old girlfriend Eve Lydon (Amy Smart). Apparently the public sex scene in Crank made her more sexually adventurous, and she thought he was dead (Chev learns that three months have passed, and it is revealed that the telephone message he left her at the end of the first movie was unintelligible due to the wind). In a back room, Vang has been cornered by a group of Mexican gangsters, led by Chico (Joseph Julian Soria), who shows he means business by chopping off a man's elbow. Vang agrees to let them have Chev, and apparently escapes. Chev is confronted by the Mexicans, and a gunfight breaks out. Everyone gets gunned down by Chev, except Chico, who escapes out a back door. Chev interrogates a wounded gangster, who informs him that El Huron (Clifton Collins, Jr.) is trying to kill him, but doesn't know why. Chev picks up Eve and they walk out.
Outside, he is met by a group of cops, who begin beating him down. He is weakened, but one of them inadvertently charges Chev by using a taser on him. Chev steals a cop car with Eve and another stripper in the back, who tells Chev that he should look at the Hollywood horse racetrack for Johnny Vang. They encounter a group of porn stars protesting low wages, and Chev is forced to escape, leaving Eve in the back of the cop car. In a nearby park, Chev steals an electric dog collar from a gay couple and uses it to zap himself.
Chev is about to be picked up by cops when he is picked up on a motorcycle by Venus (Efren Ramirez), who reveals himself to be Kaylo's brother. He also has Full Body Tourette's Syndrome. At first, Chev tells Venus that everyone responsible for his brother's death is dead, but this prompts Venus to leave. Wanting his help, Chev tells Venus that El Huron was involved but escaped.
At the horse tracks, Chev is losing energy. He calls Doc Miles and learns that the heart can be charged through the skin by means of friction. He rubs up on a couple of racetrack patrons (including Chester Bennington, who also had a cameo in the original film, and an old woman), but finally Eve shows up and really helps stimulate Chev. They have sex on the racetrack while the crowd cheers, and Chev is restored to full energy. Chev spots Vang and once again leaves Eve behind (much to the dismay of the crowd) and chases Vang through the parking garage. Vang escapes, however, and Chev is about to be subdued by security when Don Kim, the Chinese gangster who saved Chev's life in the first film, picks Chev up in his limo.
Don Kim informs Chev that there is a leader in the Triads named Poon Dong (David Carradine), who was in need of a heart transplant. When he heard of Chev's ability to withstand the Chinese adrenaline poison, he put out an order for Chev's heart. Don Kim then tells Chev that he wishes to return him to Poon Dong for a reward. Upon hearing this, Chev kills all of Don Kim's henchmen, including the limo driver, and shoots Don Kim several times. The limo then crashes, and Chev steals another car. Meanwhile, Eve is arrested, and Venus calls in Orlando (Reno Wilson) to assist in tracking down El Huron. Chico reports his failure to El Huron, who forces Chico to cut off his own nipples.
While driving, Chev is cut off by an ambulance. He boards the ambulance and is surprised to see the EMTs are working on Don Kim. He demands a new battery pack for his artificial heart, and the EMT is forced to stop working while he hooks it up. Don Kim dies, and Chev exits the limo upon seeing Johnny Vang on the street outside.
Chev hides, but Ria reappears and is hit by a passing car trying to get Chev's attention. Vang tries to escape in a car, but the car drives off without him, and Chev chases Vang to an electric plant, where there is a Godzilla-inspired fight where Chev and Vang (stuntmen with exaggerated, cartoon masks of the actors) fight on a tiny power-plant stage. Upon winning, Chev discovers that Vang's red cooler holds something other than his heart (something Chev claims is terribly offensive, but which is never revealed). Chev calls Doc Miles again, and learns that his heart is already transplanted into Poon Dong, but promises to find him for Chev. Chev goes to ask Johnny Vang, but Johnny Vang is shot and killed by Chico, and they knock Chev unconscious.
There is a dream sequence of sorts, showing Chev as a youngster, with his mother (Geri Haliwell) on the Luke Canard show talking about his violent tendencies as a boy. Eve is interrogated by police, but refuses to rat Chev out. Doc Miles uses his assistant Chocolate to lure Poon Dong in, and knocks him out.
Chev is awakened by electric shocks to his testicles, and is dragged by speedboat to an island where El Huron awaits. El Huron explains to Chev that he is the third Verona brother, and is very upset that Chev killed Ricky (Jose Pablo Cantillo) and Alex Verona (Jay Xcala). He says he is going to kill Chev, removing his new battery pack, but there is someone who will enjoy watching it, and drags Chev over to a white tent in the pool area, where he reveals Ricky Verona's head, being kept alive in a tank by a group of scientists, speaking in a Steven Hawking-like electronic voice. Chev is whipped for Verona's pleasure, and is about to die when Orlando, Venus, and Ria show up, each with their own group of gunfighters, and chaos breaks out. Venus attempts to take El Huron down with nunchakus.
Chev smashes open Verona's tank and kicks his head into a pond when it demands water, but starts to slow down. He climbs an electric pylon nearby and grabs the wires to recharge, but is flung off of it upon contact. Venus is fighting El Huron and is about to lose when Chev reappears, still partially on fire from the electricity. He beats El Huron to death (while still burning), and throws his body in the pond next to Ricky's head. In a hallucinogenic state, Chev then tries to hug Ria (thinking she is Eve) but accidentally sets her on fire as well, and she runs off screaming. His flesh burning and his face melting, Chev walks towards the camera, giving the middle finger to the audience in the final moment of the film.
During the first part of the credits, Doc Miles places Chev's heart back in (although we don't see what he does with Poon Dong) while Eve watches (due to the fire, Chev is covered in full-body bandages). At first, it looks like a failure, but after everyone leaves, Chev's eyes open, and his heart is heard beating.