Intelligence officer Amanda Waller assembles two Task Force X teams, colloquially known as the "Suicide Squad", which comprise Belle Reve penitentiary inmates who agree to carry out a mission in exchange for shortened sentences. Sent to the South American island nation of Corto Maltese after its government is overthrown by an anti-American regime, the teams are tasked with destroying the Nazi-era laboratory Jötunheim, which houses the secret experiment "Project Starfish". One team is almost entirely wiped out by the Corto Maltese military upon landing, with only team leader Colonel Rick Flag and Harley Quinn surviving. The ambush on the first team serves as a diversion, allowing the second team to enter the country undetected. Led by assassin Bloodsport, the surviving team consists of Peacemaker, King Shark, Polka-Dot Man, and Ratcatcher 2.

Waller orders the squad to find Flag, who escaped from the military but was captured by rebel soldiers. The team find the rebel base and massacre the soldiers, only to learn that Flag had been saved by rebellion leader Sol Soria. Despite the group's actions, Soria agrees to help them infiltrate the capital where they capture Project Starfish's lead scientist, the Thinker. Harley is captured by the Corto Maltese government and taken to the new dictator, Silvio Luna, who wishes to marry her. After learning of Luna's plans to use Project Starfish, Harley kills him and escapes. She joins the others, who use the Thinker to break into Jötunheim and begin rigging it with explosives.

Flag and Ratcatcher 2 enter the Project Starfish laboratory with the Thinker and find Starro the Conqueror, a giant starfish-like alien that creates smaller versions of itself to kill people and control their bodies. The Thinker explains that Starro was brought to Earth by the U.S. government, which has secretly funded the experiments for decades using Corto Maltese citizens as test subjects. An enraged Flag decides to leak a hard drive containing evidence of this, but is killed by Peacemaker, who is under orders from Waller to cover-up the U.S.'s involvement. Meanwhile, a skirmish between the rest of the team and the military leads to Polka-Dot Man accidentally setting off the explosives prematurely. As Jötunheim crumbles, the drive falls into Ratcatcher 2's possession. Peacemaker attempts to execute her for knowing the truth about Starro, but Bloodsport shoots him and takes the drive.