The film opens five years after the ending of Don: The Chase Begins Again, with Don (Shah Rukh Khan) narrating the story. The European drug cartel bosses meet in the French Riviera to discuss a new threat emerging from Asia: Don is jeopardising their business by undercutting their prices, and the bosses decree that Don must die. Living in Thailand for the last five years, he goes to a remote settlement to pick up a shipment of cocaine. Instead of the expected uneventful transaction, Don fights his way out. He returns to Malaysia, surrendering to Roma (Priyanka Chopra), who has joined Interpol, and Inspector Malik (Om Puri). Don is sentenced to death and sent to prison, where he meets old rival Vardhan (Boman Irani). He offers Vardhan a partnership, and they escape from prison after poisoning the other inmates.
In Zurich Don meets trusted companion Ayesha (Lara Dutta), and they retrieve the contents of a locker accessible only by Vardhaan. In it is a tape of J.K. Diwan (Alyy Khan), vice-president of the Euro-printing DZB (Deutsche Zentral Bank), who was sent by Fabian Kohl to bribe Singhania (Rajesh Khattar) to kill a competitor; Singhania was killed by Vardhaan five years earlier. Don blackmails Diwan into giving him the bank’s blueprints so he can steal the printing plates. Diwan misleads him and hires Abdul Jabbar (Nawab Shah), a deadly assassin. Don escapes, however, and baits Jabbar to working for him. With no other choice, Diwan gives Don the blueprints.
Don and his team plan and execute a bank robbery, taking hostages. After stealing the printing plates he is betrayed by Vardhaan and Jabbar, but escapes. However, Sameer (a team member, played by Kunal Kapoor) calls the police and Don is arrested; he threatens Sameer for informing on him. Unable to enter the bank and free the hostages, the police are forced to work with Don in exchange for giving him German immunity.