The game was officially revealed on May 1, 2012, following a set of leaked information released during the previous months. In this new world, four survivors - Samuel Stuhlinger, Abigail "Misty" Briarton, Marlton, and Russman - have banded together to survive in Washington with the help of a bus driven by a robotic driver. Beyer is an artist working for Nerve Software, "a Dallas-based independent developer" which has "helped" with previous Activision games including Black Ops in 2010.

If all of the Strike Force missions were completed, China and the United States will ally, ending the Second Cold War. Section locates and attacks Menendez at a military checkpoint and pins him down, now deciding whether he should execute or apprehend him. David, now a DEVGRU Lieutenant Commander codenamed Section, spearheads an effort by JSOC to neutralize Menendez.

Realizing her father has been corrupted by the Aether, Samantha reaches out to an alternate version of him, who resides in Dimension 63.

Known as League Play, the mode allows players of similar skill level to be matched together, and play according to the rules of Major League Gaming. A cutscene is played, showing Samantha with a boy named Eddie inside a house playing with toys of the characters who have appeared in the Zombies game mode throughout all three games. However, the Earth begins shaking, and Maxis explains to the four that he is beginning the process of the destruction of the Earth and humanity to reach Agartha, where he believes Samantha is; in the non-canon ending, the group aids Richtofen, letting him gain unlimited power over the Aether and the Earth, allowing him to kill Maxis and condemn Samantha's soul to eternal damnation. The Japanese release of the Wii U port is only the dubbed version since the console was not available in Japan in November.On December 12, 2012, all Xbox 360 Season Pass holders received access to the Nuketown Zombies map, with PC holders following on January 17, and PlayStation 3 holders on January 19, having been delayed two days due to PSN technical issues. The events of the player's ending are determined on the fates of Menendez, Lynch, and Alex Mason, and whether the Strike Force missions were completed. If the player is successful, Kravchenko discloses that Menendez has moles inside the CIA, before Woods executes him. Known as "Strike Force missions", these branching storylines appear during the 2025 storyline and feature permanent death.