Mass Effect 3 is an action role-playing game in which Commander Shepard leads a final campaign against the Reapers, a machine race that has invaded Earth and is conquering civilizations across the galaxy. Players recruit squad members from various species and classes, forge alliances, and make choices that determine which characters survive. Combat features squad-based tactics with combinable biotic and tech powers, blind fire, and enhanced melee attacks.

The game includes a cooperative multiplayer mode where up to four players fight waves of enemies to liberate conflict zones. Progress in multiplayer contributes to war preparedness in the single-player campaign. New and returning squad members join Shepard's team, including soldier James Vega and EDI, an AI in a physical body.