Marcus and Mike are forced to confront new threats, career changes, and midlife crises as they join the newly created elite team AMMO of the Miami police department to take down the ruthless Armando Armas, the vicious leader of a Miami drug cartel.

Marcus Burnett is a henpecked family man. Mike Lowrey is a footloose and fancy free ladies' man. Both Miami policemen, they have 72 hours to reclaim a consignment of drugs stolen from under their station's nose. To complicate matters, in order to get the assistance of the sole witness to a murder, they have to pretend to be each other.

Detectives Marcus Burnett and Mike Lowrey of the Miami Narcotics Task Force are tasked with stopping the flow of the drug Ecstasy into Miami. They track the drugs to the whacked-out Cuban drug lord Johnny Tapia, who is also involved in a bloody war with Russian and Haitian mobsters. If that isn't bad enough, there's tension between the two detectives when Marcus discovers that playboy Mike is secretly romancing Marcus’ sister, Syd.

After their late former Captain is framed, Lowrey and Burnett try to clear his name, only to end up on the run themselves.