Trama

In 1968, the first successfully-bonded Big Daddy is reawakened to save his Little Sister from the clutches of Rapture's new leader, Sofia Lamb.

New Year's Eve in 1958 depicts the first ever successfully bonded Big Daddy/Little Sister pairing, Subject Delta and Eleanor Lamb, respectively. Delta and Eleanor are wandering Rapture when a group of Splicers ambush Eleanor, Delta rushes in and is hit with a hypnotize Plasmid and Eleanor's mother, Sofia, appears. She hands Delta a pistol and orders him to shoot himself.

In 1968 Delta is resurrected in a Rapture Vita-Chamber, a now adolescent Eleanor is communicating with him through telepathy, asking for his help. After an encounter with a Big Sister, a Little Sister turned adolescent and merged with a diving suit, Dr. Brigid Tenenbaum contacts Delta through his radio and instructs him to see her at the train station. Delta finds Tenenbaum, she has returned to Rapture because little girls from the surface are being adducted and turned into new Little Sisters, additionally, Delta is bonded to Eleanor for life, if either strays too far, Delta's heart will stop. Tenenbaum leaves with unturned/saved girls and Delta is giving guidance over to business man and con artist, Augustus Sinclair.

Throughout the story Eleanor assigns Little Sisters to leave weapons/Plasmid drops in strategic locations to further his journey. Sofia Lamb is a former missionary turned psychiatrist that the late Andrew Ryan hired to help those struggling to life underwater, but Sofia brainwashed her patients against Ryan and form a cult known as The Rapture Family. Sofia opposed Ryan in political debates, turning the citizens against him. Eventually, Ryan urged Sinclair to remove her, Sinclair hired a reporter, Stanley Poole to infiltrate the Family and spy on Sofia, Poole reported that Sofia was attempting to overtake Rapture which was enough to have her arrested and sent to Persephone Penal Colony, while Eleanor was left in the care of Sofia's lieutenant, Grace Holloway, a jazz singer.

Poole took over the Family and lived hedonistically in Dionysius Park, squandering Lamb's finance's. Eleanor, whom never trusted Poole, confronted him, so he sent her to Little Sisters Orphanage, unknown to him, she would be transformed into a Little Sister. Furthermore, there were reports the Lamb had escaped custody, which would lead to Family members telling of his behavior, so he flooded Dionysius to eliminate witnesses.

Sofia's goal is to use ADAM to turn Eleanor into a superhuman intelligent, capable of following Sofia's altruistic ideal without any sense of self. While Sinclair, acting for himself, intends to sell Rapture's advanced technology on the surface ludicrous profit.

Delta's journey causes him to make a stop at Pauper's Drop, where Grace resides, she's resentful to Delta for once breaking her jaw for approaching Eleanor which ended her singing career. Delta confronts Grace in her hiding space and takes an override key, here, the player is given a choice to kill or spare Grace. If the latter, Grace will begin to question her loyalty to Sofia. Delta ventures on, facing more of Sofia's followers in the form of spliced and mad priest Father Simon Wales, Delta defeats Father Wales in battle and moves onto Dionysius. Here Delta encounters Poole, Eleanor reveals his actions which led to her transformation. Delta has a choice to kill or spare Poole, then carry on.

Delta arrives at Fontaine Futuristics, where scientist, Gilbert Alexander, has taken over, having been driven insane from high ADAM consumption. Delta obtains a key to Persephone from Alexander, whom asks for his life ended due to ADAM distorting his mind and body horrendously. Once again, Delta can choose to kill or spare Alexander.

Now in Persephone, Delta finds Eleanor sleeping in a quarantine chamber, with Sofia watching over her. Eleanor had been disobeying Sofia's teachings, intent only on reuniting with her Big Daddy. Her telepathy allowed her to see through Delta's eyes and witness his actions, the Little Sisters he saved/harvested and the people he spared/killed and wishes to be like him. Sofia suffocated Eleanor with a pillow which stops Delta's own heart and his body is taken to a medlab.

Eleanor is still alive and sends a Little Sister inject Delta with a special plasmid which allows him to control Little Sisters, Eleanor requests he bring her a Big Sister suit. Once changed into the suit, Eleanor breaks Delta out of confinement and plot their escape on Sinclair's private bathysphere. First, they have to get the launch card from Sinclair whom has now been forcibly transformed into a Big Daddy, so Delta kills him. Sofia has placed explosives around Persephone to halt them, with her Family and goal crumbling she chooses to die with her Family. Delta and Eleanor head for the pod, yet there is an explosive trap waiting, Eleanor teleports out of the blast, yet Delta is critically injured.

Delta is dragged up to the surface with the bathysphere, Eleanor is in the flooded bathysphere with Sofia, depending on Delta's actions, Eleanor can either provide breathing equipment to Sofia or drown her.

On the surface, the ending varies depending on Little Sisters dealt with.

If all saved, Eleanor will extract Delta's ADAM making him part of her, Eleanor stares out to a clear, serene ocean with the Little Sisters by her side.

If some were saved and others harvested, Delta can choose whether or not to die, Delta will either prevent Eleanor from extracting ADAM and be dropped into the ocean, leaving Eleanor alone. Or he can let her take the ADAM, Eleanor will be left standing over a Splicer corpse infested stormy seas.

If all harvested, Eleanor will take the ADAM by force, Eleanor will standing over a Splicer corpse infested stormy seas, ready to take on the world with her new genetically modified powers.