In the aftermath of Superman's death, intelligence officer Amanda Waller convinces the US Government to greenlight Task Force X, a response team made up of criminals and supervillains. The team will be used to combat metahuman threats, under Waller’s control via nanite bombs implanted in each criminal’s neck, which can be remotely detonated. If their missions are fulfilled, the criminals will have their sentences shortened.

Dr. June Moone, an American archaeologist, becomes possessed by a demonic witch called Enchantress. Waller is able to control the Enchantress by seizing her magical heart, which wounds her if it is struck. Waller’s subordinate Colonel Rick Flag falls in love with Moone, who is made a member of Task Force X. However, Enchantress betrays Waller, conquering Midway City, transforms the populace into monsters, and summons her brother Incubus to help her in a plan to wipe out mankind.

Task Force X is formed to stop Enchantress, using inmates from Belle Reve Special Security Barracks. The roster consists of hitman Deadshot, who wants to reunite with his daughter Zoe; Harley Quinn, a former psychiatrist-turned-girlfriend of Gotham crime lord Joker; Australian thief Captain Boomerang; pyrokinetic ex-gangster El Diablo; mutant cannibal Killer Croc; and mercenary Slipknot. The team are led by Flag, and are joined by his associate Katana, a Japanese swordswoman. Waller and Flag deliberately hide the latter’s relationship with Moone.

Upon arrival in Midway City, the team’s helicopter is shot down, forcing them to travel on foot. Boomerang convinces Slipknot to make his escape, believing the bombs are a ruse, but Flag kills Slipknot when he tries to escape. Scaling a skyscraper, the team discover Waller is their mark, trying to cover up her involvement in Enchantress’ revolt. Meanwhile, the Joker learns of Harley’s predicament, locates A.R.G.U.S. scientist Dr. Van Criss, and blackmails him into disabling Harley’s bomb.

As Waller and the squad await for a helicopter extraction, the Joker intervenes, disables Harley’s bomb, and helps her escape. Waller shoots down the Joker’s helicopter, though Harley survives and rejoins the squad, assuming the Joker is dead. Learning of Waller’s location, Enchantress kidnaps her to regain her heart. Deadshot finds Waller’s confidential files, discovering Flag’s relationship with Moone. The team abandon Flag, sharing a drink in an abandoned bar, where El Diablo reveals his powers and criminal lifestyle led to the deaths of his family. Flag relieves the squad of their mission, but, realizing they have the opportunity to prove themselves, the group set out to save the city.

The squad locate Enchantress in a flooded subway station, where Killer Croc and Flag’s platoon of Navy SEALs plant bombs beneath the subway. El Diablo embraces the demonic nature of his pyrokinesis, sacrificing himself to allow the bomb to destroy Incubus. Enchantress offers the squad to join her, which Harley appears tempted by, though uses it as a ruse to cut out Enchantress’ heart. Enchantress is defeated and Flag crushes her heart, killing her and releasing Moone from her control. Waller appears, removing ten years off each squad members' sentence and rewarding them with requests (except for Boomerang). The Joker, alive, breaks into Belle Reve and rescues Harley.

In a mid-credits scene, Waller meets with Bruce Wayne, who agrees to aid her reputation in exchange for government files on the growing metahuman community, in order to build his own superhero team. He tells Waller to shut down Task Force X.
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