Immediately after the events of the previous film, Chev Chelios (Jason Statham) lands in the middle of an intersection after falling out of a helicopter. He is scooped off the street via snow shovel by a group of Chinese medics and removed from the scene. Chev 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 white cooler with a padlock, and place a clear plastic artificial heart in his chest. He wakes up sometime later and escapes. He notices a yellow battery pack is attached to him. After a gunfight and interrogation of a thug, he learns the location of Johnny Vang: the Cypress Social Club.
Chev calls Doc Miles (Dwight Yoakam), who says that Chev has been fitted with an AviCor artificial heart. Miles informs Chev that once the external battery pack runs out, the internal battery will kick in and he will have 60 minutes before it stops working. While driving Chev crashes his car which destroys his external battery pack. After getting directions from a driver, Chelios has the driver use his jumper cables on him. At the club, Chev loses Vang but picks up a hooker named Ria (Bai Ling) who sends him to a strip club where Vang is hiding out. In the club, Chev finds Eve (Amy Smart), now a stripper (It is humorously revealed that the phone call Chev made to Eve while falling to his supposed death at the end of Crank was completely incomprehensible due to the wind rushing by, and the farewell he had left on her answering machine was merely how he imagined it would sound). A group of Mexican mobsters, led by Chico, show up looking for Chelios. After a gunfight, Chev learns that a mobster named "El HurÃ³n" ("The Ferret") wants to kill him, but he doesn't find out why.
Outside of the strip club, Chev commandeers a police cruiser with Eve and another stripper. The stripper tells Chev that he should look at the Hollywood Racetrack for Johnny Vang. Along the way, Chev meets Venus (Efren Ramirez), who reveals himself to be Kaylo's brother. Wanting his help, he tells Venus that El Huron was involved in his brother's death, but escaped. At the horse track Chev begins losing energy again. Another call from Doc Miles informs him that friction will cause static electricity to power the internal battery. Eve shows up and they have sex on the racetrack before Chev spots Vang and leaves Eve behind. Vang escapes, and Chev is about to be subdued by security when Don Kim picks Chev up in his limo. He informs Chev that there is a leader in the Triads named Poon Dong (David Carradine), who was in need of a heart transplant and chose Chev's to replace his. Chev kills Don Kim and his henchmen upon learning that Don Kim wishes to return him to Poon Dong for a reward. Meanwhile, Venus calls in Orlando (Reno Wilson) to assist in tracking down El Huron.
While searching for Vang, Chev boards an ambulance and steals a battery pack for his artificial heart. Chev exits the ambulance upon seeing Johnny Vang on the street outside and a shootout ensues before Chev subdues Vang. Chev discovers that Vang's red cooler doesn't contain his heart and then learns via cellphone from Doc Miles that his heart has already been transplanted into Poon Dong. Johnny Vang is shot and killed by Chico as Chev interrogates him, after which Chev is knocked unconscious. Doc Miles uses his secretary to locate Poon Dong to retrieve Chev's heart.
Chev is taken to an island where El Huron awaits. It is revealed that El Huron is, in fact, the brother of Ricky and Alex Verona, both of whom Chelios killed in the first film. He reveals Ricky Verona's head is being kept alive long enough to watch El Huron kill Chelios. El Huron is about to kill Chelios when Orlando, Venus and Ria show up, each with their own group of gunfighters, and a fierce gunfight ensues. Chev kicks out Rick Verona's disembodied head in the nearby swimming pool. Venus engages El Huron in a fight before he can kill Chev. As he starts to slow down, Chev climbs a nearby electric pole and grabs a pair of live wires to recharge. He is flung off the pole and set on fire by the massive current. He returns with that power, just in nick of time to save Venus, and kills El Huron. Chelios walks towards the camera, giving the middle finger to the audience.
Doc Miles replaces Chev's heart. At first it looks like a failure, but Chelios's eyes open wide and his heart monitor indicates normal activity.
Who replaces Chev's heart ?
Doc Miles replaces Chev's heart