In the game, players obtain a Pip-Boy, a computerized wristwatch which allows the player to access a menu with statistics, maps, data, and items. Players can also find game cartridges, which can be played on the Pip-Boy. Another returning gameplay feature is the Vault-Tec Assisted Targeting System (V.A.T.S.), which plays an important part in combat. While using V.A.T.S., real-time combat is slowed down, and action is played out from varying camera angles in a computer graphics version of "bullet time". Various actions cost action points, limiting the actions of each combatant during a period of time, and the player can target specific body areas for attacks to inflict specific injuries; head shots can be used for quick kills or blinding, legs can be targeted to slow enemies' movements, and opponents can be disarmed by shooting at their weapons. Unlike in previous games, in which the player had a random chance to inflict a critical hit, they can now be done at will with a button press. However, the option requires a recharge afterwards.

When players start the game, they are given points to spend on a character progression system called the SPECIAL system. The system represents seven statistics, namely strength, perception, endurance, charisma, intelligence, agility and luck. When players gain enough experience points to elevate to a new level, they can unlock a new ability. When players allocate more points to a stat, more abilities can be unlocked. These perks can also be upgraded to improve the protagonist's efficiency and to further unlock new abilities. There are about 275 perks available for players to unlock. In the game, players can recruit companions, who stay and accompany players and provide assists. Players can only take one companion at a time. There are 12 recruitable companions, some of whom can be romanced by the player.