In 1957, Colonel-Doctor Irina Spalko and a convoy of Soviet agents posing as U.S. soldiers infiltrate a military base in the Nevada desert. They force Indiana Jones to lead them to a crate in "Hangar 51", which holds the remains of an extraterrestrial creature that crashed ten years before in Roswell, New Mexico. Indiana attempts to escape but is foiled by his partner Mac, who reveals that he is working with the Soviets. After a fight and an elaborate vehicle chase through the warehouse, Indiana escapes on a rocket sled into the desert, where he stumbles upon a nuclear test town and survives a nuclear blast by hiding in a lead-lined refrigerator. While being debriefed, Indiana discovers he is under FBI investigation because of Mac's Soviet ties. Indiana returns to Marshall College, where he is offered an indefinite leave of absence to avoid being fired because of the investigation. At a train station, Indiana is stopped by greaser Mutt Williams and told that his old colleague, Harold Oxley, disappeared after discovering a crystal skull near the Nazca lines in Peru. Indiana and Mutt go to a local diner, where they discuss Akator (also known as El Dorado), Crystal Skulls, and the Ugha tribe. Mutt passes Indiana a letter from Oxley. Soviet agents approach them, and a chase commences on the college grounds. Indiana realizes that the Soviets were trailing Mutt to get him to decode Oxley's letter.
1957. Indiana Jones (Harrison Ford) e seu ajudante Mac (Ray Winstone) escapam por pouco de um encontro com agentes soviéticos, em um campo de pouso remoto. Agora Indiana está de volta à sua casa na Universidade Marshall, mas seu amigo e reitor da escola, Dean Stanforth (Jim Broadbent), explica que suas ações recentes o tornaram alvo de suspeita e que o governo está pressionando para que o demita. Ao deixar a cidade Indiana conhece o rebelde jovem Mutt Williams (Shia LaBeouf), que tem uma proposta: caso o ajude em uma missão Indiana pode deparar-se com a caveira de cristal de Akator. Agentes soviéticos também estão em busca do artefato, entre eles a fria e bela Irina Spalko (Cate Blanchett), cujo esquadrão de elite está cruzando o globo atrás da Caveira de Cristal.