Terminator Salvation is a third-person shooter where the player needs to "constantly move, flank, cover and utilize their squad to progress." The player must battle Skynet enemies from the film of the same name as well as new enemies specifically designed for the game.

The game features a campaign that can be played alone or cooperatively with one other local player via split-screen. The co-op version of the game enables players to play as both John Connor and his teammate Blair Williams.

The game employs a cover and movement system not unlike those featured in Gears of War and Brothers in Arms: Hell's Highway, wherein the player can quickly choose to dodge between different forms of cover, coming out only to fire shots at enemies. Staying in cover is advantageous, as the player only regenerates health when they have not received damage for a certain amount of time (as in the Halo and Call of Duty games). Although players initially are only equipped with an M4 carbine, other weapons such as the RPG-7 and M79 grenade launcher, Remington 870 shotgun, and M249 SAW as well as various types of grenades (Flash and fragmentation) are acquired throughout the game. Enemy A.I. is relatively strong, both keeping track of the player's location realistically (that is, not omniscient but using sight and sound to locate the player) as well as actively pursuing and flanking them when cover is sought by the player.