Spacecrafts are transporting enlistees to Neo Venus Construction Inc. (NEVEC) Academy's educational institutions on the planet E.D.N. III. Bren Turner, a candidate from E.D.N. II, is on board among the new recruits when the fleet is suddenly attacked by mysterious Vital Suits. To confront the hostile forces, Instructor Walter Stingray selects Bren to pilot a prototype VS equipped with a next-generation AI, capable of autonomous behavior. As the new "master" of this state-of-the-art machine, Bren designates it with the name "Gingira" and joins Walter to defend the fleet.

The game features similar gameplay elements to previous Lost Planet games, including the presence of major boss battles, extreme terrain, and Vital Suits. The player controls the protagonist, Bren, from a third-person perspective as he is challenged to navigate through different areas by running, dashing, grappling, zip-lining, and using his jet pack to quickly boost over a short distance. Thermal energy (T-ENG) is now used for charging up special attacks and restoring the life bar, rather than for survival. Players can tap into their T-ENG reserve to release numerous forms of an exothermic (EX-T) blast to deal large amounts of damage to enemies.