Twenty years after Wolfenstein II: The New Colossus, America and much of the world is liberated from Nazi control and B.J. Blazkowicz and his wife Anya have raised their twin daughters Jessie and Zofia, teaching them how to defend themselves. In 1980, Blazkowicz mysteriously disappears without a trace. Jessie, Zofia, and their friend Abby, Grace Walker's daughter, discover a hidden room in the attic with a map indicating Blazkowicz traveled to Nazi-occupied Neu-Paris to meet the French Resistance. Believing that American authorities will not follow Blazkowicz to Nazi France, the girls steal an FBI helicopter and a pair of powered armor suits and head for France.
In France, the girls meet Juju, the leader of the Resistance, who confirms that she had met Blazkowicz, but she has no knowledge of his current location. They discover that he is trying to find a way into a secret Nazi installation called Lab X. In order to gain access to Lab X, the girls decide to help the Resistance hack the main computers of the "Brothers", a trio of security towers that hold the keys to Lab X. Upon reviewing the data in the Brothers' computers, Abby realizes that Juju is a Nazi agent and her partner is General Lothar, the disgraced commander of the Nazi forces in Neu-Paris. The girls pretend to drink Juju's drugged wine, and Lothar gloats that with the Brothers under his control, he can commence his plans to start a Fourth Reich without interference from his superiors in Berlin. A struggle ensues, with Lothar and Juju managing to escape while Abby is stabbed in her left eye.
Abby directs Jessie and Zofia to find Lab X. She explains that the Nazi leadership attempted to kill Lothar for disobeying their orders, forcing him into hiding where he eventually infiltrated the French Resistance with Juju. Jessie and Zofia breach Lab X and proceed to its deepest level, where they find Blazkowicz. He tells them that after he killed Hitler in the 1960s, he accidentally activated a doomsday device that will eventually render the Earth uninhabitable. He traveled to Lab X to find a way to stop the doomsday device, where he learned about the existence of multiple alternate dimensions, and glimpsed one where the Nazis lost World War II. He then uses a Da'at Yichud artifact to upgrade Jessie and Zofia's powered armor suits and directs them to go after Lothar. Meanwhile, Lothar retakes his old headquarters and orders his allies in Berlin to stage a coup against the government. Jessie and Zofia confront Juju and Lothar and kill them both.
Afterwards, Anya and Grace arrive. Realizing the threat the Fourth Reich poses, Blazkowicz, Anya, and Grace decide to call upon all their allies around the world to fight the Fourth Reich. Jessie, Zofia, and Abby decide to stay in Paris to defend it against the Fourth Reich's inevitable counterattack.