The game takes place six months after the events of Driv3r. It is revealed that both John Tanner and Charles Jericho survived the shootout in Istanbul. In the game's trailer, it is revealed that since then, both men have recovered and Jericho has escaped to San Francisco, while Tanner and his partner; Tobias Jones have pursued him there. Jericho is shown being transported in the back of a prison truck, but manages to escape with a vial of acid hidden within his mouth by a paid off guard. He overpowers the guards, and hijacks the truck. Tanner and Jones witness this from Tanner's car, pursuing Jericho as he causes havoc on the streets of the city. Tanner ends driving in front of Jericho in an alleyway, who, using the truck rams Tanner's car into the path of a tractor trailer, resulting in a devastating crash, putting him into a coma. The majority of the game takes place in Tanner's coma dream.
Whilst in a coma dream, Tanner soon discovers his ability to "shift" into another person's body, retaining his persona but, to everyone else, looking and sounding exactly the same as the person he has shifted into. Using this confusing power, Tanner helps some teenagers win street races to get money for college fees, aids some vigilante ex-cops remove fake medicine from circulation and lends his driving abilities to police officers hunting down criminals whilst trying to figure out Jericho's plan. After deducing that Jericho is after the materials to create a cyanide gas bomb, he shifts into Ordell, a low-time crook looking to rise up through Jericho's organization.