On July 14, 2520, a mysterious object called the Stone-Like has been unearthed, along with a non-functioning robot. The secretary of defense, Chief Igarashi, orders both to be examined. Up in Earth's atmosphere, Captain Tengai of the Tetra issues the ship's pilots Buster, Reana, and Guy to test the three Silvergun prototype fighters. As Igarashi relays information on the Stone-Like and the robot, he notes the robot dates back to the prehistoric era and has the same identification tags as the robot aboard the Tetra, C.R.E.A.T.O.R. 00104, and Tengai wonders if this is mere coincidence. Suddenly, the Stone-Like mysteriously activates and destroys the facility where it is excavated. It quickly overwhelms Earth's forces and wipes out all life on the planet. Only the crew of the Tetra survives since they were above orbit. One year after humanity's destruction, on July 13, 2521, the Tetra returns to Earth since it is running out of food and supplies.
The story is told in a non-linear perspective, beginning with Stage 3, "Return". As the Tetra arrives on Earth, the pilots are sent out to investigate in their respective Silverguns. Stage 2, "Reminiscence", is a Flashback, where the Tetra and the Silverguns fly to the Earth defense headquarters to see Chief Igarashi, prior to the Stone-Like's attack. Since Igarashi knows that the Stone-Like cannot be defeated by conventional means, he orders the Tetra and her crew to escape to Earth's orbit just as the Stone-Like unleashes its attack on Earth.
Back in the present, the Stone-Like, now aware of the Tetra and the Silverguns' presence, sends out its forces to destroy them (Stage 4, "Evasion"). Tengai orders C.R.E.A.T.O.R. to head for the Earth defense headquarters to gather information regarding the Stone-Like, only for the artifact to intercept the group at the headquarters. In Stage 5, "Victim", the Silverguns face off against two battleships orbiting headquarters, intending to stop C.R.E.A.T.O.R. from completing its mission from its intel gathering. The battleships are destroyed, but the Stone-Like attacks the headquarters directly. Tengai manages to keep the structure from falling with the Tetra, and C.R.E.A.T.O.R. boards Reana's Silvergun while Guy pulls a suicidal attack on the Stone-Like, but to no avail. Tengai orders Buster and Reana to escape while he orchestrates a similar, yet futile feat against the Stone-Like with the Tetra. In a last ditch attempt, Buster persuades Reana to join him in destroying the Stone-Like; before they head out to space, C.R.E.A.T.O.R. asks to take it back to the surface and requests from both of them a particular item.
In Stage 6, "The Origin", the Stone-Like locates Buster and Reana and engages them, while briefly explaining its actions: humanity's tendency to destroy and their nature to commit war forced the Stone-Like to awaken and bring about the apocalypse. Eventually, the Stone-Like, after being defeated in combat, transports the two Silverguns back in time to the year 10,000 B.C. In Stage 1, "Link", the Stone-Like unleashes its power in a cataclysmic explosion. Buster and Reana are unable to escape, swallowed up by the blast, seemingly destroyed. 20 years in the future, C.R.E.A.T.O.R. has been hiding in an underground facility, and with strands of hair from Buster and Reana that it asked of them before their departure, begins the process of creating their clones. The Stone-Like has been deactivated, its power exhausted from the previous battle.
In its last moments before its internal power is extinguished, C.R.E.A.T.O.R. surmises from the data it gathered from Earth defense headquarters: the Stone-Like is the guardian of the Earth, seeking to see to the planet's advancement and evolution, along with its inhabitants and their way of life. If the Stone-Like deems that things must start over, it will destroy the Earth and repeat the cycle again until humanity can come to realize their inherent nature and change for the better. C.R.E.A.T.O.R.'s purpose comes full circle - to ensure humanity will survive through their clones, and with that, the robot collapses and ceases function. The story of Radiant Silvergun ends as the clones of Buster and Reana awaken from their cloning tubes.