The game is set in an era of space colonization where the Helghast Empire has recovered from its defeat in the First Helghan War and launched a blitzkrieg against the outer Interplanetary Strategic Alliance (I.S.A.) colony planet Vekta. Vekta's orbital Strategic Defense (S.D.) platforms failed during the initial assault, allowing the Helghast to land swarms of soldiers onto the surface and making it all the more difficult for the outnumbered I.S.A. forces.
In the game, the Helghast are a faction of human descendants who colonized the planet Helghan many generations ago. The planet's harsh environment forced the Helghast to adapt and mutate so much that they can no longer be considered human. They are stronger, faster and more resilient than their human cousins, and possess a burning hatred for humanity. Except for a small number of half-breed Helghast and trained troopers, they require a gas mask and air processing tank that creates air similar to that found on the planet Helghan.
The player takes control of I.S.A. Captain Jan Templar, who is fighting off the Helghast invasion. Templar and his squad are called back to the base for reassignment, and are promptly sent to find the I.S.A. operative Gregor Hakha and the information in his possession. During the course of the game, the player also takes control of several other characters, such as Shadow Marshal Luger (a female special operations assassin), a heavy weapons specialist Staff Sergeant Rico Velasquez (a Helghast-hating soldier with an itchy trigger finger), and Colonel Hakha, a half-Helghast, half-Human spy.

As the game progresses the player discovers that General Stuart Adams, a high ranking ISA officer, is a traitor and a servant of Joseph Lente (the commanding General of The Third Helghast Special Forces Army) and was responsible for sabotaging the SD platforms, rendering them unable to defend against the Helghast. The Earth Defense Fleet (EDF) go to assist the Vektan Army, however Adams kills General Voughton and receives his security key, allowing him to reboot the platforms, and prepare an ambush for the EDF relief force.
Jan and the others confront Lente, only to find out that Hakha was a commander in chief for him. Lente says that Hakha's family was ashamed to even be related to him, except his brother who talked of his heroism. Because of this, Lente had Hakha's brother shot down. With anger in his eyes, Hakha shoots Lente dead.
The team fly to the central SD platform and confront Adams, who is wounded by Templar. The platform begins to break up and Adams is killed by falling debris while trying to escape. Finally, the team restore the SD platform, allowing the EDF fleet to fight off the Helghast.