In 1946, World War II still rages on. The Nazis have turned the tide of the war against the Allies after having developed advanced technologies. Captain William "B.J." Blazkowicz, aided by pilot Fergus Reid and Private Probst Wyatt III are dispatched in a massive air raid against a fortress run by Wilhelm "Deathshead" Strasse, an old personal enemy of Blazkowicz and the man responsible for this sudden technological revolution. Despite a valiant effort by Blazkowicz and the rest of the team raid quickly goes south, as the raid meets almost insurmountable resistance from Deathhead's personal forces. Eventually only Blazkowicz, Wyatt, Fergus, and a small handful of other survivors are the only ones able to penetrate the fortress defenses, and before they can fulfil their objectives of assassinating Deathshead blowing up the base, they are captured inside a human-experiments laboratory by some of Deathhead's Super Soldiers. There, Deathshead shows personally up to gloat a bit, before forcing Blazkowicz to choose who he will kill, either Fergus or Wyatt, before leaving Blazkowicz and the survivor to die in an incinerator. They make their escape by blocking the incinerator's exhaust pipes, and forcing open a nearby window, which allows them to jump into the sea. But the overloaded incineration explodes just as Blazkowicz makes the jump and he is hit shrapnel in the head, causing him to suffer a critical injury, knocking him unconscious. Miraculously, he avoids drowning and is fished out of the sea by some Polish fishermen, but a result of his head injury, Blazkowicz is stuck in a catatonic state, and therefore gets sent to an asylum in Poland, where he remains in this vegetative state and is taken care of by Anya Oliwa, the daughter of the head physician.
Stuck in an semi-conscious state, Blazkowicz spends fourteen years in the asylum, only dimly aware of the passage of time. In 1960, the Nazis order the asylum to be shut down, killing the patients and executing Anya's mother and father when they protest against this, while Anya is taken captive. As Blazkowicz helplessly watches his fellow patients being ruthlessly murdered, his anger grows, and just before he himself is about to be executed, he breaks out of his vegetative state from sheer rage and stabs his would-be executioner to death. Despite the years of inactivity having put their marks on his body, Blazkowicz is able to fight his way through the extermination squad send to clear out the asylum, and manages to capture their rather cowardly officer and making his escape in the officer's vehicle alongside Anya. They then drive to Anya's grandparents' farm, where they reveal to Blazkowicz that the Nazis had won the war after forcing the United States to surrender in 1948, and all known Resistance members in Europe have recently been captured. Blazkowicz later interrogates the captured officer about the location of Resistance members held in Berlin before brutally executing him with a chainsaw. Anya's grandparents then smuggle Blazkowicz and Anya through a checkpoint in Stettin before the pair continue on their own towards Berlin.
On the train ride, Blazkowicz starts a romantic relationship with Anya and has an encounter with the unusually unpleasant and sadistic high-ranking Nazi officer, Frau Engel, and her younger personal assistant and lover, Bubi, who themselves are headed towards Berlin for business. Ostensibly for a bit of "fun", Engel decides to test out what she claims is a new kind of "racial purity test" on Blazkowicz to determine if he really is as Aryan as his appearance would seem into imply. In reality, the test is Engel overtly baiting Blazkowicz to try and steal her gun, so she can have an excuse to kill him for giggles; but when he doesn't fall for the bait, Engel grows bored and frustrated and lets him pass.
The train soon arrive in Berlin, and Blazkowicz breaks into the prison, where he rescues the survivor he spared years ago (either Fergus or Wyatt). The survivor then leads him and Anya to the secret headquarters of the surviving Resistance movement in Berlin, which turns to be a revived Kreisau Circle, led by Caroline Becker, who was previously thought to be dead in Isenstadt and is now left paralyzed.
Inspired by Blazkowicz's return and daring rescue of the survivor, the Resistance decides to step up its activities and launches an attack on a Nazi research facility in London, where they steal secret documents and prototype stealth helicopters. It is soon revealed that the Nazis have been developing their technology through an ancient organization called Da'at Yichud, which created inventions such as energy weapons, computer AI's, and super concrete. It's also revealed that someone had been tampering with concrete's formula, which makes it susceptible to mold deterioration. The Resistance finds out about a former Da'at Yichud member named Set Roth, who is currently imprisoned at a labor camp in Belica, which turns out to be run by Frau Engel. Blazkowicz goes undercover in the camp and meets with Set, who tells him that Nazi Germany stole and co-opted technology and research developed by him and the Da'at Yichud, which turns out to be a secret society of Jewish scientists, to produce the machines that won the war, and offers to help the Resistance should Blazkowicz destroy the labor camp. Blazkowicz agrees and finds a battery that can power a remote control secretly developed by Set, but is captured by Frau Engel, who recognizes him from the train. As Blazkowicz and Set are about to be executed, he secretly hands Set the battery. Set uses the battery to remotely control the camp's largest robot, which then proceeds to disfigure Engel before freeing the two, allowing them to destroy the camp and liberate its prisoners
Set reveals to the Resistance that the Nazis' discovery of Da'at Yichud technology is what allowed Germany to turn the tide against the Allies and win the war. Set reveals the location of one cache, but they will have to use a U-boat to reach it. With Set's help, Blazkowicz is able to break into the Nazi regime's munitions storage deep inside the Berlin catacombs, where he obtains a U-boat, but it's discovered that it's the flagship of the Nazis' submarine fleet, and is equipped with cannons that can fire nuclear warheads, which can be activated through the use of codes from the Nazi lunar base to operate. Blazkowicz uses the technology called Spindly Torque, a sphere used to destroy super concrete, to steal the identity of a Nazi lunar scientist to infiltrate the lunar base. He obtains the codes, but on his way back to Earth, find that Frau Engel and Deathshead has raided the Resistance's main hideout, capturing Anya and Set in the process. He evacuates the Resistance hideout with Caroline and the survivor, escaping to the U-Boat.
Later, the Resistance uses the nuclear codes and the Spindly Torque to launch an assault on Deathshead's compound. In the process, Bubi ambushes Blazkowicz and injects him with a sedative, hoping to prove his love for Frau Engel by killing Blazkowicz as she watches via a remote camera. Due to his head injury, however, Blazkowicz is able to shake off the effects of the sedative and turns the tables on Bubi, viciously killing with his own knife as Frau Engel watches in horror. Blazkowicz then rescues and evacutes the captured Resistance members and makes it to the top of the tower, confronting Deathshead at his laboratory. There, Deathshead greets Blazkowicz and reveals that he possesses the brain of the soldier Blazkowicz chose to die. The robot comes alive and attacks Blazkowicz, and Blazkowicz defeats the robot then puts his friend to rest by destroying the brain. Deathshead then attacks Blazkowicz personally piloting a larger robot against him. Blazkowicz destroys the robot then drags a wounded Deathshead out of the cockpit. He stabs Deathshead, who in as a last spiteful action reveals a hidden grenade on his person which soon detonates. The explosion kills Deathshead and mauls Blazkowicz. As a wounded Blazkowicz crawls to safety, he mentally recites The New Colossus as he watches Caroline, Set and Anya evacuate the prisoners from the beachhead below. Blazkowicz orders the Resistance to fire the nuclear cannon as the game ends. After the credits, a helicopter is heard approaching.