In A.D. 2642, Earth remains scarred from previous alien conflicts as environmental problems grow beyond humanity's control. 80% of the planet's population was completely devastated by a malfunctioning hyper-magnetic weapons grid during development. Bill Rizer, the hero of the Alien Wars, was held responsible for the incident, as well as for murdering his partner, Lance Bean, who reportedly tried to stop him. He was given a sentence of 10,000 years in cryogenic prison.

However, five years later, in 2647, Earth faces another threat as the terrorist organization "Blood Falcon", led by a mysterious and superhuman commander, spreads panic over the world. The ruling government, referred to as the "Triumvirate", decides to release Bill Rizer prior to completing his sentence, in view of his previous successes in defending Earth, in hope of neutralizing Blood Falcon. Lucia, an advanced cyborg soldier built by the government from Dr. Geo Mandrake's research, is sent to accompany and assist Bill's endeavors. Bill eventually finds out that Lance is still alive and is in fact the commander of Blood Falcon himself.

After defeating Lance, it is revealed that the aliens from the past games attacked because the Triumvirate secretly stole a mysterious, powerful "Relic" from them. With this information, Bill and Lucia have to confront Triumvirate and uncover the secret of the alien Relic.