A sting operation to capture arms dealer Miles Jackson goes awry when the FBI's inside man double crosses them. Miles rendezvouses with his girlfriend Erica Kessen, who has a getaway car. Officers Danny Fisher and Hank Carver are dispatched to help the FBI. They look at Jackson's record and see a surveillance video of him dancing with Kessen. An encounter with them at a traffic light leads to her death and Miles being taken away. Miles swears vengeance on Fisher.
One year later Fisher, now promoted to Detective due to his actions with Jackson, gets a phone call from Jackson, who has escaped from prison. Fisher runs outside the house looking for Jackson, and Fisher's car and house explode, throwing him to the ground. After Fisher recovers, Jackson says he is launching a game of revenge called "12 Rounds." The house, the car, and Phil, the plumber who came to fix a pipe were "Round 1." Molly Porter, Fisher's girlfriend is kidnapped by Jackson for "Round 2." For "Round 3," Fisher and Carver must follow a series of clues to locate the cell phone that Jackson calls, and for "Round 4" Fisher has to get to New Orleans Savings and Loan where a fire has broken out and extract two security deposit boxes within 20 minutes.
Carver has a lead on the man who helped kidnap Molly Porter and volunteers to look into that while Fisher continues with the game. FBI Special Agents George Aiken and Ray Santiago work with them to get Porter back.
For "Round 5" one of the security boxes is a bomb and the other contains a clue to the next round. Fisher discovers and disposes of the bomb. The other box contains a hotel room key. The room is raided and found empty. For "Round 6," Fisher and the FBI go to the Monteleone Hotel to find Molly and Miles in a room, but when they arrived, Miles had only left on a video camera of the hotel a note that said "we are still here". After that, Danny talks to Willie; a hotel employee who knew where Miles was later. But at that moment, the security elevator stops and they finds a video recording with Molly (at gunpoint) saying that in 60 seconds the elevator will fall (telling Willie that what he does to her is not personal) and that (given that Wille is overweight) only one will survive. When Danny leaves the elevator, Willie falls and dies (still subtracting 5 seconds)
In "Round 7" Fisher follows a series of clues to a bus where he finds Porter on board, wearing a bomb underneath her jacket. He is handcuffed to a bar and is given an envelope with a phone number as the clue to the next round. The Feds try to get Jackson but he escapes with Porter. When Fisher is freed, he tells the Feds about the bomb, and just when a sniper shot trying to kills Miles, fail and everyone get out of the bus (including Molly and Miles). Carver shows up and tells Fisher he has located Jackson's henchman, Anthony Deluso. In "Round 8" Fisher has to find the correct cell phone number that disarms bombs placed in different locations. Jackson answers and tells him that his call disabled Streetcar 907's brakes. In "Round 9" Fisher and Santiago slam their car into the transformer, shutting off electricity for the whole neighborhood. They run along the streetcar, clearing people out of the way until it can slow to a halt.
A mine planted by Jackson kills Carver and Deluso. Jackson says that Porter's bomb can only be disarmed by Fisher's fingerprint. He tells Fisher to pay a visit to Erica Kessen, so Fisher, Santiago, and Aiken start for the cemetery. Another detective, Chuck Jansen calls Fisher to tell him that the numbers in the envelope were rigged to the streetcar. Jackson had cameras monitoring the elevator shaft and set off the bomb five seconds early. Fisher realizes that Willie's death in the elevator episode was orchestrated by Jackson. Santiago does a check on Willie and finds he had a second job as a Homewood Security guard. They figure out that Jackson was leading them to take out the power because Homewood Security comes in to move the federally unprotected cash from the United States Mint in New Orleans. Jackson's grudge against Fisher was only a cover for his scheme to steal this money.
Aiken tells Santiago to lock down the Mint, while he and Fisher go after Porter. Fisher realizes that "Round 12" is a wild-goose chase, since Jackson needs Porter, a nurse, to help him escape. Jackson, dressed as a security guard, steals the cash. He uses Porter's ID card to get to a Medevac chopper on a hospital roof, transporting the money inside a body bag. Fisher and Aiken race to the hospital roof, where Aiken is wounded. Jackson activates the touch phone-bomb and throws the switch away. Porter and Fisher jump into a pool, while Jackson is left in the exploding helicopter. The movie ends with Danny and Molly leaving, with Molly wanting to go home, but Danny tells her about what happened to it.
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