Fallout 3 sidequests are optional quests that exist outside of the main quest and story lines. Those you opt to play, as well as the choices made during the sidequests, can affect other game elements including the game's ending.

One of the earliest side quests in Fallout 3 is found in the town of Megaton. There's a live nuclear warhead in the center of the town, and the local police ask you to disarm the bomb. However, another character, Burke, asks you to do the opposite and set the bomb off. He offers a large sum of money. The choice you make could mean the loss of other sidequests and be a setback in the main objective of finding your father. Keeping Megaton around will allow players access to all of the town's people, and what the have to offer. This can include quests, items, information and allies.

Fallout 3 takes place in a post-apocalyptic Washington DC in the United States. The main character lives in a fallout shelter called Vault 101 with his father. After his father mysteriously ventures out of the vault, the player heads out of the vault in search of him.

As an open-ended RPG, Fallout 3 gameplay emphasizes character attributes and customization, as well as decision making and tactical combat. Player decide which character attributes to improve throughout the game. Attributes include intelligence, strength, weapon skills, perks and bonus attributes. The player's choices largely determine the outcome of the game. There are over 1,700 versions of the final cutscene based on a combination of the main character's actions.

The game can be played from both a third and first-person perspective. Combat makes use of both modernistic sci-fi weaponry and melee weapons. Fighting is in real time, but can be paused with use of the in-game VATS system. The VATS system allows the player to select different enemy body parts to attack. The effectiveness of each possible attack is displayed on the interface. All actions cost action points, lending an RPG aspect to the gameplay.

Fallout 3's Karma system measures the choices the player makes and adjusts the way non-player characters respond to him.