Intelligence officer Amanda Waller assembles two Task Force X teams—colloquially known as the Suicide Squad—that comprise Belle Reve penitentiary inmates, who agree to carry out missions for Waller in exchange for lighter sentences. They are sent to the South American island nation of Corto Maltese after its government is overthrown by an anti-American regime, and are tasked with destroying the Nazi-era laboratory Jötunheim which holds a secretive experiment known as "Project Starfish". One team is led by Waller's subordinate Colonel Rick Flag and is almost entirely wiped out by the Corto Maltese military upon landing. This distraction allows the other team to enter the country undetected. The second team is led by assassin Bloodsport, who accepted the mission in order to prevent his daughter from being incarcerated at Belle Reve, and consists of Peacemaker, King Shark, Polka-Dot Man, and Ratcatcher 2. They find Flag at a base camp for rebel soldiers and convince rebellion leader Sol Soria to assist them.

Harley Quinn survives the attack on the first team and is taken captive by the Corto Maltese government. She learns of the new regime's plans to use Project Starfish against other nations. In the Corto Maltese capital, the second team captures the Thinker, the lead scientist in charge of Project Starfish. Harley escapes and joins the others, who use the Thinker to break into Jötunheim. Most of the Squad rigs the facility with explosives as Flag and Ratcatcher 2 enter the underground laboratory with the Thinker. He reveals that Project Starfish is Starro the Conqueror, a giant alien starfish that creates smaller versions of itself to kill people and take control of their bodies. Starro was brought to Earth by the U.S. government, who have been secretly funding experiments on him in Corto Maltese for the past thirty years using thousands of the island's citizens as test subjects. An enraged Flag decides to leak a hard drive containing evidence of this revelation but is killed by Peacemaker who is under secret orders from Waller to cover up the U.S.'s involvement in the experiments. Meanwhile, a skirmish between the Squad and the Corto Maltese military leads to Polka-Dot Man accidentally setting off the explosives prematurely. As the facility falls apart, Peacemaker attempts to execute Ratcatcher 2 for knowing the truth about Starro, but Bloodsport shoots him and takes the drive.

Starro escapes the destroyed laboratory, kills the Thinker and much of the military, and begins taking control of the island's population. Waller tells the Squad that their mission is complete now that Jötunheim is destroyed, but Bloodsport chooses to ignore her and leads his teammates in battling Starro, while Waller is knocked out by her subordinates to prevent her from executing the squad. During the battle, Polka-Dot Man is killed, Harley pierces a hole in Starro's eye, and Ratcatcher 2 summons the city's rats to chew the alien to death from the inside. With the military diverted, Soria takes control of the government and pledges democratic elections. Bloodsport forces Waller to release him and his surviving teammates from their imprisonment in exchange for keeping the contents of the drive confidential, and the Squad is airlifted out of Corto Maltese.

In a post-credits scene, Peacemaker is shown to be alive and under the supervision of Waller's subordinates.
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