In 1957, at the height of the Cold War, Indiana Jones finds himself entangled in a Soviet plot. After narrowly escaping a disputed encounter with Soviet agents led by the ruthless Irina Spalko in a remote Nevada warehouse housing top secret artifacts, Jones returns to his job as a college professor. However, his respite is brief, as he is soon drawn back into adventure when a rebellious young man named Mutt Williams seeks him out with a personal plea. Mutt reveals that his mother, who turns out to be Indy's old flame, and a colleague have been kidnapped while on the trail of a mysterious and mythical object - a crystal skull believed to possess psychic powers and point the way to El Dorado, the fabled City of Gold.

Compelled by loyalty and the allure of the unknown, Jones joins Mutt on a journey to the remote corners of Peru. Pushing through the dense Amazonian jungles, they encounter treacherous terrain, hostile forces, and ancient puzzles that tap into Indy's extensive knowledge of archaeology and history. As they piece together clues and dodge Soviet agents hell-bent on acquiring the powerful artifact for their own nefarious purposes, the duo learn that the crystal skull must be returned to its rightful place in a lost city to unlock its secrets and avoid catastrophe. Their quest is a race against time, as both allies and enemies close in, and the true nature of the skull's power becomes increasingly evident.