The game starts off 32 years after the events in Descent: FreeSpace. The player is a pilot in the Galactic Terran-Vasudan Alliance (GTVA), a single entity formed to cement the alliance between the Terran and Vasudan races. However, opposition still exists to this union, and a faction of Terrans led by Admiral Bosch formed the Neo-Terran Front (NTF) and has rebelled, taking over several star systems. The player's early missions are to quell these rebellions and bring in Admiral Bosch. After a few missions, the Shivans are encountered again, and the GTVA has to handle these aliens and crush the NTF.

A hook is introduced with the introduction of the GTVA's latest ship, the enormous capital ship, the GTVA Colossus. Dwarfing even all other capital ships, this juggernaut class ship's power is exhibited to the player as it easily destroys the NTF's fleet. The high tone of the story is maintained as missions keep showing off the Colossus' victory after victory, climaxing with its victory over the Shivan juggernaut equivalent, the SJ Sathanas. There is a sudden reversal of fortune as it is revealed there are many more Sathanas juggernauts, and the GTVA is forced to retreat.

The plot device of using a tremendous explosion within a jump node to seal it off in Descent: FreeSpace is re-used here near the end of the campaign. The GTVA has decided to seal off a node to stop the Sathanas horde's advance. Their plan is to send in a bomb-laden ship into the only node in the Shivans' path and remotely detonate it. This becomes a pyrrhic victory, as the GTVA loses the Colossus, their only match for the Sathanas. The finale of the game features the player in a mission to defend the fleeing ships from Shivan attacks. In the midst of the fighting, the system's star is detected to be going supernova, and the player can choose to flee the scene. If the decision is to stay and die defending the remaining ships, a small heroic tribute is paid to the player's character in the ending.