The movie opens up with Dominic Toretto hijacking fuel tankers in the Dominican Republic. After a heist, he believes that the trail is too hot and leaves his girlfriend Letty to go elsewhere. He is in Panama City when he gets a call from his sister Mia. She tells him that Letty has been murdered. Dom heads back to Los Angeles and examines the car crash that Letty was in and finds traces of nitromethane. Dom then goes to the only car mechanic that uses nitromethane and coerces him into giving him the name David Park, the man who ordered the fuel.
Meanwhile, FBI agent Brian O'Conner is trying to track down a drug dealer named Arturo Braga. His search leads him to David Park. Dom arrives at Park's apartment first and hangs him out of the window by his ankles before letting go. Brian, who also at that time was on his way to Park's house, saves Park and Park becomes the FBI's new informant. Park gets Brian into a street race through Los Angeles; the winner will become the last driver on a team that traffics heroin between the United States-Mexico border for Braga. Dom is also at the race. At the end, Dom and Brian are neck-and-neck, and Dom wins when he hits Brian's rear fender and causes him to spin out. Brian uses his power as an FBI agent to arrest another driver, Dwight Mueller, and takes his place on the team.
The day after, the team meets Fenix, one of Braga's men, and they drive across the border. During a tense standoff, Dom blows up his car, Brian hijacks a Hummer with 60 Million dollars worth of heroin, and both Dom and Brian drive back to Los Angeles. They hide the heroin in a police impound lot. The next day, Brian tells his superiors that he can lure Braga into a trap, forcing him to personally show up to exchange money for the heroin, so that the police can arrest him. He says he will do this if they will pardon Dom. At the drop site, however, the man who claims to be Braga is a decoy and the real Braga escapes and flees to Mexico.
Brian and Dom head out to Mexico on their own to catch Braga. They find him at a church and apprehend him. As Braga's henchmen come down to rescue their leader, Brian and Dom drive through the underground tunnels back to the United States. During the final moments of the chase, Brian, who is with Braga, crashes his car and is injured after being T-boned by Fenix at the end of the tunnel. Before Fenix has a chance to shoot Brian, Dom, who was not far behind, drives into and kills Fenix. Shortly after, on the US side, police and helicopters start streaming to the crash site. Brian tells Dom to get out of there, but Dom says he is tired of running and had already attained his only mission of avenging Letty. Despite Brian's request for clemency, the judge sentences Dom to 25 years-Life. In the last scene of the movie, Dom is loaded into a prison bus that will take him to Lompoc penitentiary. As the bus drives down the road, Mia, Brian, along with Tego and Rico (who assisted in the Dominican Republic heists), arrive in their cars to intercept it.