At the start of the game, player-character Jack is a passenger on a plane that goes down in the Atlantic Ocean in 1960. As the only survivor, Jack makes his way to a nearby lighthouse that houses a bathyscaphe terminal that takes him to Rapture.
Jack is contacted by Atlas via radio, and is guided to safety from the Splicers. Atlas requests Jack's help in stopping Ryan, directing him to a bathysphere where he claims Ryan has trapped his family. When Jack encounters a wandering Little Sister and its Big Daddy, Atlas urges Jack to kill the Big Daddy and kill the Little Sister to harvest her ADAM for himself; Dr. Tenenbaum overhears this and intercepts Jack before he harms the Little Sister, urging him to spare the child, providing him with a plasmid that would force the sea slug out of her body. Jack eventually works his way to the bathysphere, but Ryan destroys it before Jack can reach it.
Enraged, Atlas directs Jack towards Ryan's mansion, battling through Ryan's Splicers and facing against more deranged citizens. Ultimately, Jack enters Ryan's personal office, where Ryan is patiently waiting for Jack by casually playing golf. Ryan explains that Jack is his illegitimate child, taken from his mother by Fontaine who placed him out of Ryan's reach on the surface, and genetically modified to age rapidly. Jack was revealed to unknowingly be a sleeper agent, conditioned to accept the code phrase, "Would you kindly", which would force him to blindly act out any instruction that followed the phrase. Fontaine had planned to use Jack as a trump card in his war with Ryan, bringing him back to Rapture when the time was right; Jack's genetics would allow him to access systems, such as the bathysphere, that Ryan had locked out long ago. Ryan accepts his death by his own free will, and uses Jack's conditioning to force him to kill him with the golf club. After doing so, Jack becomes aware that the "Would you kindly" trigger has preceded many of Atlas' commands, and that Jack was himself responsible for crashing his plane near the bathysphere terminal after reading a letter containing the trigger. Atlas contacts Jack, revealing himself to be Fontaine; without Ryan, Fontaine takes over control of Ryan's systems, and leaves Jack to die via security drones released into Ryan's office.
Jack is saved by Dr. Tenenbaum and the Little Sisters who had previously been rescued. Dr. Tenenbaum helps Jack to remove Fontaine's conditioned responses, including one that would have stopped his heart. With the help of the Little Sisters, Jack is able to make his way to Fontaine's lair to face him. Fontaine, being cornered by Jack, injects himself with a large amount of ADAM, becoming an inhuman monster. Jack is able to better Fontaine after fighting him and draining his excess ADAM three times, at which time the Little Sisters subdue Fontaine's body to extract the ADAM, eventually killing him.
Three endings are possible depending on how the player interacted with the Little Sisters, all narrated by Dr. Tenenbaum. If the player has rescued all the Little Sisters, the ending shows five Little Sisters returning to the surface with Jack and living full lives under his care, including their graduating from college, getting married, and having children; it ends on a heart-warming note, with an elderly Jack surrounded on his deathbed by all five of the adult Little Sisters.
In the case where at least one Little Sister was harvested, the ending shows Jack turning on the Little Sisters to harvest their ADAM. Tenenbaum sadly narrates what occurred, condemning Jack and his actions. The ending then shows a George Washington-class nuclear submarine coming across the wreckage of the plane. The submarine is suddenly surrounded by bathyspheres containing Splicers who immediately attack the crew and take control of the submarine, ending with a close-up of the radiation symbol on the submarine. The tone of Tenenbaum's voice is more hostile if the player had harvested every Little Sister.
