In the aftermath of Superman's death, government official Amanda Waller assembles Task Force X, a covert team of dangerous criminals from Belle Reve prison for high-risk missions in exchange for clemency. The squad, implanted with explosive devices in their necks to ensure compliance, includes elite hitman Deadshot, former psychiatrist turned crazed villain Harley Quinn, pyrokinetic gangster El Diablo, opportunistic thief Captain Boomerang, monstrous cannibal Killer Croc, and the mysterious enchantress June Moone, whose body is possessed by an ancient witch, Enchantress. Waller assigns Rick Flag, a Special Forces soldier, to lead the team along with his sword-wielding bodyguard, Katana.

The team's first mission comes swiftly, as Midway City becomes besieged by a horde of mutating humans under the control of a powerful adversary. Task Force X is dispatched to extract a high-profile mark, wading through an urban warzone while grappling with their own anarchic tendencies and the Joker's attempts to reunite with his beloved Harley Quinn. As they progress, personal motives and histories emerge, forcing each member to confront their past and the possibility of redemption, defining the nature of true villainy and heroism against the backdrop of chaos and the imminent threat to the world.