As part of the Borderlands series, Borderlands 3 is centered on the planet Pandora, which has been long-rumored to contain Vaults holding vast amounts of treasure and technology, left behind by a mysterious alien civilization known as the Eridians. In decades prior, several corporations and bandit clans have laid siege to Pandora to try to find the Vaults, but the constant conflict and bloodshed has left the planet and its population ravaged and crazed. However, there are still those independently searching for the Vaults, known as Vault Hunters (the player characters).
Borderlands 3 takes place seven years after Handsome Jack's death in Borderlands 2 and the downfall of the Hyperion Corporation in Tales from the Borderlands. In Borderlands 2, it was discovered that numerous other Vaults exist on other planets in the galaxy. In the power vacuum left by the defeat of Jack and Hyperion, twin siblings Troy and Tyreen Calypso form the Children of the Vault (COV), a violent cult of personality formed from the remnants of the planet's many bandit factions, to gain possession of the other Vaults, specifically one called 'the Great Vault'. Lilith, one of the playable Vault Hunters from the first game and current leader of the Crimson Raiders, a resistance force created to protect Pandora, recruits new Vault Hunters to help stop the Calypsos.
Several characters from past Borderlands games make a return. Previously playable Vault Hunters Claptrap, Zer0, Maya, Brick, and Mordecai appear as NPCs assisting the player. Aurelia, Sir Hammerlock's sister and one of the playable Vault Hunters in Borderlands: The Pre-Sequel, also appears as a boss. Returning NPCs include gun salesman Marcus Kincaid, explosives expert Tiny Tina (now going by just Tina), Miss Mad Moxxi and her mechanic daughter Ellie, cyborg hunter Sir Alistair Hammerlock, archaeologist Patricia Tannis, weapons manufacturer Mr. Torgue, and Crazy Earl. Rhys Strongfork, one of the two playable protagonists in Tales from the Borderlands, and his best friend Vaughn also appear. Timothy Lawrence, a body double of Handsome Jack and one of the playable Vault Hunters in The Pre-Sequel, and Gaige, one of the playable Vault Hunters in Borderlands 2, are featured as NPCs in the game's DLC campaigns.