19年后，印第安纳琼斯博士（Harrison Ford饰）再次启程，旨在将埃克托王国遗失的水晶骷髅头骨归还原地——传说中，归还圣物者将被赐予巨大力量。 　　在琼斯的老友奥克斯发现水晶头骨前，这一切还只是传说。可奥克斯之后却不知何故丧失了心智，并落入苏联特工队的手中。为首的冷酷女间谍艾瑞娜（Cate Blanchett饰）深深着迷于所谓的神秘力量，她胁迫琼斯一行人与其共同前往亚马逊流域，找寻失落的黄金城埃克托王国。 　　在秘鲁密林，琼斯等人和苏军展开酣畅淋漓的战斗，其间还伴随着沼泽、食人蚁、原始土著攻击等致命威胁，在他们历经千难万险，最终踏入密室的那一刻，世界上最奇异的景象出现了……During the Cold War, Soviet agents watch Professor Henry Jones when a young man brings him a coded message from an aged, demented colleague, Harold Oxley. Led by the brilliant Irina Spalko, the Soviets tail Jones and the young man, Mutt, to Peru. With Oxley's code, they find a legendary skull made of a single piece of quartz. If Jones can deliver the skull to its rightful place, all may be well; but if Irina takes it to its origin, she'll gain powers that could endanger the West. Aging professor and young buck join forces with a woman from Jones' past to face the dangers of the jungle, Russia, and the supernatural.