Fallout 4 is an open world role-playing game in the style of its predecessors, Fallout 3 and Fallout: New Vegas. Returning gameplay features include the ability to switch between first-person and third-person perspectives, an open world with free roam exploration, a variety of combat options (including guns, explosives, unarmed, and melee), numerous side quests along with a more linear main questline that branches toward its conclusion, dialogue options that influence the route of a conversation, and the selection of companions that aid in battle.

The S.P.E.C.I.A.L. skill system also makes a return, allowing the player to decide the importance of certain skills to their character (S.P.E.C.I.A.L. being an acronym for Strength, Perception, Endurance, Charisma, Intelligence, Agility, and Luck) upon leveling up. The function of perks is altered, as they are now attached to a skill tree with availability dependent on the rank of the S.P.E.C.I.A.L. skills that they're associated with. The Intense Training perk is replaced by the optional ability to improve the rank of any one of the S.P.E.C.I.A.L. skills by leveling up, in the place of selecting a perk. The Pip-Boy can be acquired early on, and provides access to the player's statistics, inventory, maps, and quest information as in previous games, with the added function of playing mini-games that can be found throughout the Commonwealth. The player can also make use of the Pip-Boy app in order to access the Pip-Boy menu, rather than using the in-game function. HP (health points) and AP (action points) make a return as primary statistics, with the removal of weapon and armor condition. Stimpaks, beds, and other types of consumables such as water or TV dinners can be used to restore HP. Unlike in previous games, exposure to radiation directly influences the player's max health, and can only be reduced through RadAway or paid assistance from a doctor. AP restores over time, and can be used to sprint or attack using the Vault-Tec Assisted Targeting System (V.A.T.S.), slowing down time and giving the player the ability to select a target with success in combat dependent on accuracy, which itself is dependent on factors such as weapon range, distance of the target, and obstruction of the target.

New features include the absence of a level cap, allowing the player to completely max their skills and acquire all perks, fully-voiced male and female protagonists, and an expansive crafting system. The player can cook food, craft drugs, add a wide variety of modifications to weapons and armor, and construct functioning settlements. Settlements may be provided with food, purified water, power, defense systems, housing, and shops that attract merchants and settlers. The player can obtain materials for building by collecting objects that may be deconstructed throughout the wasteland (classified in the Pip-Boy as "junk") or deconstructing unneeded objects, such as collapsed houses or fallen trees, all of which can be placed in the workshop for later use.

The story of Fallout 4 begins in 2077, in an alternate retro-futuristic timeline that diverged from that of the real world following World War II. In favor of miniaturization of electronics, the world's governments have focused on developing nuclear energy as a power source, which has led to the creation of power armor, laser weaponry, and housekeeping robots. However, despite these technological advancements, the world is in a state of crisis, as resources are scarce and nuclear war is imminent. During this time, the customizable player character lives a peaceful life in a suburban neighborhood in Boston, Massachusetts with their spouse and infant son. However, the peace is interrupted when a Vault-Tec representative knocks on the family's door. The man informs the player character that their family has recently been approved for entry into the nearby Vault 111, one of many vaults constructed by Vault-Tec as shelter against the threats of a nuclear holocaust. This visit is closely followed by a news report of a nuclear attack, giving the family no other choice but to take shelter in Vault 111, where they are tricked into a state of cryosleep. 210 years later, in the year 2287, the player character emerges from the vault, beginning their journey into a post-apocalyptic wasteland.