In the prologue, the ISA has set up their fleet of Cruisers, including the New Sun, in the clouds of Helghan over the Helghast capital city, Pyrrhus, preparing for a final assault to take the city. Unable to get their capital ships close to the city and destroy it with bombardment due to Helghast anti-aircraft firepower, the ISA deploys an invasion force. The ISA's troops, including Alpha Team (with the player character), are deployed in an attempt to capture the city. The invasion is seemingly successful until the Helghast activate their main defense system, a barrier of electric arc towers throughout the city, killing many ISA soldiers and crippling the first wave of the assault, reducing the ISA's advance to a crawl; however, the fight between the ISA and Helghast continues with unmitigated ferocity as the slowly retreating Helghast desperately repel the ISA forces whose compelling advances seize Visari Square in a climactic and pulsating battle.
Using an intact piece of an arc tower destroyed earlier in the campaign, scientist Evelyn Batton discovers that the arc towers are powered by an element called Petrusite, and large portions of the mysterious element are located around the Tharsis Refinery on the outskirts of Pyrrhus. The refinery is thought to be abandoned. Alpha Team is ordered to accompany Evelyn and travel to the outskirts of the city in an attempt to find a way to disable the towers.
During the mission, Sev and Rico depart from the team in order to activate a communications tower. Before the tower is activated, however, Garza, Natko and Evelyn are captured by Helghast. Eventually, Sev and Rico find their squad, only to see Colonel Mael Radec, a ruthless Helghast commander, interrogating the group in the hopes of obtaining the launch codes for the Helghast's stolen set of ISA nuclear warheads. After the squad refuses to give information to Radec, he loses his patience and threatens to execute the group. While Sev, realizing the danger of rushing into the fray, waits and attempts to find a good location to ambush Radec's unit, Rico's impatience causes him to rush in, attempting to save the squad. Unfortunately, Garza is mortally wounded in the ensuing firefight, and Radec escapes. The only thing the squad can do is return to the New Sun before they are attacked again. Evelyn heads to the nearest communications tower to call for extraction. The squad is then attacked by more Helghast troops, but the group is able to fend off the attack. Unfortunately, when ISA support finally arrives, the injured Garza collapses and dies in Sev's arms.
Back aboard the New Sun, Sev mourns for Garza; however, he is interrupted by a surprise Helghast counter-attack on the ISA fleet; initially ISA had established orbital control militarily but the Helghast breached them. All ships, including the New Sun, are boarded. In the assault, Colonel Radec reaches the bridge where he personally executes Evelyn and mortally wounds Fleet Commander Colonel Jan Templar. Before leaving, Radec steals the nuclear strike codes for the (previously stolen) nuclear weapons. Templar, in a final act of self-sacrifice, manages to deactivate the thrusters on the New Sun, sending it crashing onto Tharsis Refinery, destroying the city's Petrusite defense grid.
With the defence grid deactivated, the ISA advance and attempt to regroup near Visari's palace in Pyrrhus with victory in their scents; however, a nuclear bomb is deliberately detonated within the city by the Helghast, destroying it, liquidating most of the ISA forces. With the fleet decimated largely, and the ISA ground campaign crippled by the blast, Alpha team and the last remaining ISA troops attack the palace of Scolar Visari with only a small shard of hope, confronting relentless waves of a fanatical Helghast resistance raining blows upon them.
The ISA troops manage to breach the palace and Sev and Rico try to fight their way to Visari's throne room, but encounter Radec and his personal guard en route. Sev and Rico manage to eventually eliminate Radec's guard after a ferocious battle, but are then forced to battle Radec himself, who decides to duel the two interlopers personally. Eventually, the two manage to severely injure Radec who commits suicide to avoid capture.
Finally, Sev and Rico, still under orders to capture Scolar Visari and deliver him to the Vektan high command, find the Helghan leader waiting for them in his throne room. He tells Sev and Rico that the war is far from over and seemingly goads them to kill him, telling them that in death the Helghast will remember him as a martyr, and subsequently unleash terrible vengeance upon the remaining ISA forces; his survival is all that is keeping the Helghast "under control".
Rico, determined to avenge Templar and Garza, the latter of whom died due to Rico's own errors, and has left him wrought with guilt, falls for Visari's provocation and guns the Helghan Emperor down. As Visari succumbs to his injuries, he mutters his last words: "The madness...begins."
Worn from what he has been through and disillusioned with Rico's execution of Visari, Sev leaves the palace and sits on the entrance steps. There, he sees an overwhelmingly giant fleet of Helghast ships, which were believed to be destroyed by the first ISA wave, initiating an assault on what is left of the ISA fleet and sees, first hand, the destruction Visari envisioned.