Assuming control of Subject Delta, a hulking Big Daddy, players are tasked with fighting through Splicers, the psychotic human population of the city, using weapons and an array of genetic modifications. The game also includes a story-driven multiplayer mode that takes place during Rapture's civil war, before the events of the first game.

BioShock 2 was chiefly developed by 2K Marin, with 2K Australia, Arkane Studios, and Digital Extremes providing additional support. The story received major changes over the course of development. Garry Schyman, the composer of the first game, returned to create the score for BioShock 2.

BioShock 2 begins on New Year's Eve 1958. Subject Delta, a Big Daddy, patrols Rapture with Eleanor, his Little Sister. Eleanor's mother, Sofia Lamb, separates the pair and forces Delta to kill himself. Delta awakens in 1968, resurrected by Little Sisters under the control of Eleanor.