Indiana Jones is an adventurer archeologist. The time is the late 1950s, and he and his friend George "Mac" Michale Ray Winstone have just been captured, by a group of communist agents led by Irina Spalko (Cate Blanchett), who have infiltrated America. Their goal: Jones must get the remains of the crash of an extraterrestrial ship, from the secretive Area 51 of Nevada. Then, Michale is revealed as a helping agent of the enemy.
However, Indiana Jones manages escaping from them, reaching an area of the desert, over which atomic-bomb experimentation is going on; Indiana gets there just to the final countdown, escaping into a lead-furnished refrigerator, which is hurled in the air some miles away. Indiana gets out of it unharmed.
The FBI then goes after Indiana Jones, suspiciously about Michale, whose ties with the Communists are being investigated, and after he allegedly helped the enemy into a secret American base. Indiana then is virtually fired from Marshall College, owing to this.
Indiana Jones also meets one of his students, Mutt Williams (Shia LaBeouf), who tells about Harold Oxley (John Hurt) his mother Marion Ravenwood (Karen Allen); all captive after finding a mysterious crystal skull at South America. In accordance with the legend, whoever brings the skull back to the mythical city of Akator would possess all its supernatural powers.
Disregarding the FBI then, both Indiana Jones and Mutt manage to escape to Peru, following Marion's clues. At a cavern of Nazca, near its uncanny ground drawings, they find a mysterious crystal skull, which is magnetized. However, the Communist agents show up again, capturing them, and bringing them to their Brazilian base.
There, Indiana Jones finally meets Marion, who results Mutt's biological mother; Indiana is his biological father thusly. During the following transportation, Indiana and his fellows manage disentangling off their captivity into the Amazon jungle. They are chased, and eventually they fall down from an humongous cascade, right before another cave, which had been clued by the ancient sources.
After confronting the quite hostile Ugha aborigines, they sneak into a chamber with thirteen crystal alien skeletons, of which one lacks a crystal head. Fitting the previously found one to it, the crystal statues come alive and the reality gets twisted, as all the rocks of the temple start twirling around. A portal to another dimension has just opened; unlike their Russian foes, who perish, Indiana Jones deems that it's time to leave. They do so just in time, as the whole valley plunges down before their eyes, and a massive spaceship emerges.
Back in America, having his college job back, Indiana Jones gets finally married to Marion.