After a successful run of hijacking fuel tankers in the Dominican Republic, Dominic Toretto (Vin Diesel) has become an international criminal. Under increasing pressure from the local police, Dom's partner Han (from the third film) decides to flee to Tokyo. Dom also knows he has to flee. He refuses to allow Letty (Michelle Rodriguez) to run away again with him. Because he is worried of the repercussions of her being found with him when he is cornered by the FBI. (The prologue ends here.)
Some time later, Letty is found to have been shot dead in her wrecked car. Dom returns to the scene of her murder just outside of L.A.. There, he discovers traces of nitromethane, which allows him to lead a personal investigation up to a certain David Park, who had purchased the nitromethane for the driver who killed Letty. Park is coerced into helping Dom get a spot in a street race, arranged by Ramon Campos, where he will supposedly find Letty's killer.
Meanwhile, Brian O'Conner (Paul Walker), now an FBI agent, is assigned to track down a notorious drug lord named Arturo Braga. Brian's investigation also leads him to David Park. He arrives at Park's apartment while Dom is still interrogating him. At the FBI bureau, Park also tells Brian that the aforementioned street race grants the winner a spot on the team that traffics heroin across the United States-Mexico border for Braga. Dom and Brian participate in the race, and Dom wins. Having lost the race, Brian uses his position at the FBI to wrongfully arrest Dwight Mueller, another of Braga's drivers, in order to usurp Mueller's spot on the team. Ramon Campos, Braga's right hand man, invites the drivers to a party, where Dom ends up in a confrontation with a driver called Fenix, and Brian looks for signs of Braga.
The next day, the team's drivers and their cars are smuggled into Mexico to receive the heroin which they are to import across the border at night. They are to meet with Fenix en route and pass through a path of tunnels to evade the surveillance systems used to monitor the borders. Gisele, Braga's liason, gives Dom a subtle warning in the form of the Spanish phrase "vaya con Dios" After the run, Dom realizes that the drivers are routinely shot and killed after each import job, to avoid having to pay them. Letty, having been in the same situation, was the only driver to get away when they shot her team. The ensuing pursuit led to her car crash and getting shot. Now, just before shooting Brian and Dom, Fenix admits with no remorse that he killed Letty. Suddenly, the cars behind them explode due to sabotage by Dom, who had anticipated the betrayal. Brian uses this diversion to hijack one of the Hummers carrying the heroin, and escape the gunfire with Dom.
Back in L.A., they hide the Hummer in the LAPD impound lot, and Brian claims that Dom now owes him a "10-second car", echoing Dom's line from the first movie. Dom smashes the window of an impounded Subaru WRX STi, which he "gives" to Brian. They go to the Torrettos' house, where Dom learns that Brian had been contacted by Letty, who had agreed to infiltrate Braga's organization to collect information in exchange for clemency for Dom, so that he could return home to her in LA. This is how she had ended up being one of the drivers for the Braga import job which led to her death. Mia forgives Brian for his past betrayal five years earlier.
The next day, he tells his superiors about his plan to lure Braga into a trap, offering him his heroin back in exchange for $6 million, which Braga is to deliver himself. However, Brian requests that the FBI pardon Dom before proceeding with the plan. Campos agrees to Brian's deal, not knowing that the FBI is poised to arrest Braga at the exchange site. However, the FBI only succeeds in apprehending Braga's decoy, realizing too late that Campos is the real Braga. Because of this error, Braga is able to evade capture and flees to Mexico, out of the FBI's jurisdiction.
Brian and Dom head after Braga on their own, and find him in a cathedral in Mexico praying for salvation. They kidnap him, but are soon chased by Braga's henchmen, to the underground tunnels where Dom's Dodge Charger crashes. Once on the U.S. side of the border, an injured Brian is about to be shot by Fenix when Dom suddenly arrives, driving a henchman's car straight into Fenix, killing him. Braga is finally apprehended by the FBI, and despite the promised clemency clause, so is Dom.
Brian appeals to the courts, but Dom is sentenced to "25 years to life without the possibility of early parole." The movie concludes with Dom being transported in a prison bus on a desert highway to the Lompoc Penitentiary, when Brian appears, driving Dom's repaired Charger, with Mia, Tego, and Rico in two other stealthy black cars, for an interception.