The film begins in 1957, during the height of the Cold War. Indiana Jones and his sidekick, Mac (Ray Winstone), are captured by Soviet agents, led by the ruthless Colonel Irina Spalko (Cate Blanchett). They are taken to a secret U.S. military base where the Soviets are searching for a mysterious artifact known as the Crystal Skull. Indiana manages to escape but soon finds himself embroiled in a larger conspiracy involving the legendary city of Akator, also known as El Dorado.

Indiana is contacted by a young greaser named Mutt Williams (Shia LaBeouf), who tells him that his old colleague, Professor Harold Oxley (John Hurt), has gone missing after discovering another Crystal Skull in Peru. Mutt also reveals that his mother, Marion Ravenwood (Karen Allen), Indiana’s former lover, has been kidnapped by the Soviets. Together, Indiana and Mutt travel to Peru, where they uncover a series of ancient clues leading them to Akator.

As they venture deeper into the jungle, they encounter various dangers, including deadly traps, giant ants, and the persistent Soviet forces. Along the way, Indiana learns that Mutt is actually his son, Henry “Mutt” Jones III, a revelation that adds a new layer of emotional complexity to their relationship.

The group eventually reaches Akator, where they discover a hidden chamber filled with crystal skeletons. It is revealed that the Crystal Skulls are actually of extraterrestrial origin, and the chamber is a portal to another dimension. Colonel Spalko, obsessed with gaining ultimate knowledge, places the Crystal Skull on one of the skeletons, triggering a massive energy surge that opens the portal. However, the overwhelming power proves too much for her, and she is disintegrated.

Indiana, Mutt, Marion, and Oxley manage to escape the collapsing temple as the portal closes, leaving behind only the ruins of Akator. In the end, Indiana and Marion rekindle their romance, and the film concludes with the two of them getting married, with Mutt looking on as their proud son.