Indiana Jones hunts down an English alchemist, a Renaissance scholar and a stolen manuscript containing the great alchemical secrets of immortality and transmuting base metals to gold.

The novel begins with Indiana Jones descending down a hillside towards the lost city of Cozán, in the rain forests of Central America.

After deciphering the clues in the pyramid, he discovers the Crystal Skull of Cozán and retrieves it, only for the artifact to be snatched away by the main antagonist, Leonardo Sarducci.

Sarducci tells Indiana Jones his plan to achieve immortality and orders his partner, Marco, to kill the archeologist.

A giant snake eats Marco and Indiana Jones escapes from the temple and returns to a village with his guide, who accompanied him in the expedition.

After dumping the load of garbage into the ocean with Indy and Alecia inside, the pair makes their way to one of the flying boats that is part of the Italian air armada AKA The Atlantici that is allowing Sarducci to travel around the globe so fast.

Because Alecia bares a strong resemblance to his deceased wife, Sarducci releases them and accidentally gives them a clue which leads them to Libya where they meet with Sallah.

In the middle of the Libyan desert, on the border to Egypt, the trio meets Prince Farqhuar who leads his rebel army to battle with the "roman pigs".