BioShock 2 takes place in Rapture in 1968, 8 years after the events of the first game. It is shown through flashbacks and audio recordings that the player character Subject Delta, the first Big Daddy created, is forced to commit suicide in 1958 by Sofia Lamb,through the use of a mind-controlling plasmid. This was done in part because Delta's Little Sister, Eleanor, is actually Lamb's daughter. Lamb, originally brought to Rapture to help psychologically-stressed citizens of the underwater city cope with the situation, used brainwashing techniques to convert her patients into a cult called "The Family", and attempted to take over Rapture. Andrew Ryan discovered this through a mole, Stanley Poole, and had Lamb thrown in prison, leaving Eleanor in the care of Grace Holloway. Eleanor eventually confronted Poole about her mother; Poole panicked and kidnapped Eleanor, leaving her in a Fontaine orphanage and eventually leading to her conversion to a Little Sister. Lamb later returned to Rapture, reclaimed her daughter from Delta, and took over Rapture after Ryan's death. Lamb guided the growth of the Little Sisters into more dangerous Big Sisters, and sent them out to the Altantic coastline to kidnap little girls and turned them into new Little Sisters for Rapture.
In 1968, Eleanor, now a teenager, has gained control over many of the Little Sisters, and uses them to revive Subject Delta at a Vita Chamber. Delta is drawn towards Eleanor by their past Daddy/Sister connection. Bridgette Tenenbaum encounters Delta, and explains that unless Delta reunites with Eleanor, a fail-safe device will trigger and put him into a coma. With the help of the Little Sisters under Eleanor's control and Tenenbaum's ally, Augustus Sinclair, Delta makes his way towards Lamb's stronghold, encountering both Poole and Holloway en route. As Delta progresses, it becomes clear that Lamb is seeking to use ADAM to transform and enslave Eleanor in the same manner that Fontaine had control over Jack Ryan. Lamb's ultimate goal is to have all the collected minds and memories of everyone in Rapture become a part of Eleanor, through the use of ADAM, thus making her an "Embodiement of the Family", which Lamb believes will put an end to "The Self".
Delta arrives at a containment cell where Eleanor is held, but Lamb captures him and severes the bond with Eleanor by rendering her unconscious. Eleanor uses the Little Sisters to bring Delta a plasmid that allow him to control the Sisters, with which he is able to bring Eleanor a complete Big Sister suit, thus allowing Eleanor to become a Big Sister. Eleanor escapes with it, rescues Delta, and together they head for an escape pod that Sinclair has arranged to leave Rapture. The two find that Lamb has converted Sinclair in a Big Daddy, and Delta is forced to finish him off. After a final climactic showdown with the remnants of The Family, Eleanor and Delta make it to the escape pod, but a final trap set by Lamb mortally wounds Delta and starts to send them to the bottom of the sea. Using the last of his strength, Delta manages to grab onto the side of the escape pod and climb on board. Trapped in the flooded escape pod with her mother, Eleanor makes the choice to either kill or save Lamb based on the player's actions.
There are several possible endings depending on how the player has performed during the game; these are based on whether the player has rescued all the Little Sisters or harvested ADAM from them, and if they have spared the lives of certain non-player characters (like Holloway and Poole) within the game. In general, if the player's actions are benevolent, Eleanor will save Lamb, and if otherwise hostile, will allow Lamb to drown. When the pod reaches the surface, Eleanor and the rescued Little Sisters find a dying Delta barely hanging onto the pod. Again, depending on the player's actions during the game, the ending will change. If the player has generally performed good deeds, Eleanor will absorb ADAM from Delta, taking her father's spirit into herself, and leaving Rapture behind forever. If the player has performed too many destructive actions, Eleanor will absorb Delta's power and use it to make herself even stronger to dominate the world. A mix of actions may leave Eleanor to opt against absorbing Delta's ADAM and mourns for Delta's passing.