The player again assumes the role of the Commander, who had up until recently been placed in alien stasis for them to make use of their strategic thinking via a brain implant. After the Commander is rescued by Central Officer Bradford, XCOM launches an attack on an alien convoy and steal an elerium core used to power the Avenger, an alien supply barge that has been converted into XCOM's mobile base.[14] In the Avenger, the Commander has the support of rogue ADVENT scientist Dr. Richard Tygan, replacing the now-missing Dr. Vahlen, and Chief Engineer Lily Shen, daughter of and successor to the now-deceased Dr. Raymond Shen, with whom the Commander was familiar in the prior game.

However, this time there are a new set of enemy aliens called the Chosen, three elite alien warriors tasked by the Elders to defeat XCOM and recapture the commander; the Assassin, which uses stealth and is able to kidnap the player's soldiers directly from the battlefield, the Hunter, an alien-human hybrid that uses long range rifles, and the Warlock, who uses psionic powers and can summon additional enemies during battle.