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.

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.