In the Aftermath of Metroid Fusion, Samus and Sylux have put aside their differences to aid revolutionary forces as the Federation tears itself apart in Civil War. But strange reports from the warlord cliques who have crawled out of the corpse of the fallen Space Pirates have drawn their attention far away from that civil conflict to the Space Pirates' dealings with forces beyond the universe.

In this quest, Samus and Sylux will find themselves catapulted to a galaxy in a distant universe. One where events orchestrated by the fascist Ecumene have had consequences reaching across many realities. And now they must strive to put an end to a dream of the annihilation of all strains of humanity. They are joined by heroes both from that universe and from other realities such as the Dinobot Grimlock or the mighty Tenno, all drawn by the scope of the Ecumene's sinister plan to tear the heavens apart to enact their genocide.