Johann Shmidt, the Red Skull, was the son of an abusive, drunken German villager named Hermann Shmidt and his saintly, long suffering wife Martha, who for years endured abuse and beatings from her husband. Martha died giving birth to Johann, their only child. Driven to madness by the death of the woman he both loved and hated, Hermann Shmidt tried to drown the newborn infant, accusing him of murdering Martha. The doctor who had just delivered the baby saved Johann from his father, and the next morning Hermann Shmidt committed suicide. The doctor took Johann to an orphanage, where the child led a lonely existence. Johann ran away from the orphanage when he was seven years old and lived in the streets as a beggar and a thief. As he grew older he worked at various menial jobs but spent most of his time in prison for crimes ranging from vagrancy to theft.

In his late teens during the rise of the Third Reich, Schmidt got his most prosperous job, a bellhop in a major hotel. There he served the rooms of Adolf Hitler himself. By chance, he was present when Hitler was furiously berating an officer and swore he could train Johann himself, a simple bellhop, to be a better National Socialist. Looking closely at him and sensing his dark inner nature, Hitler decided to take up the challenge and recruited Schmidt.

Dissatisfied with the standard drill instruction his subordinates used to train Schmidt, Hitler took over personally. Upon completion, Hitler gave Schmidt an unique uniform with a grotesque red skull mask, and he emerged as the Red Skull. His role was the embodiment of Nazi intimidation, while Hitler could remain the popular leader of Germany. The Red Skull was appointed head of Nazi terrorist activities with an additional large role in external espionage and sabotage. He was spectacularly successful, wreaking havoc throughout Europe in the early stages of World War II. The propaganda effect was so great that the United States government decided to counter it by creating their own equivalent using the recipient of the lost Project Rebirth, Steve Rogers, Captain America.

The two counterparts soon clashed in what would be a series of engagements throughout the war, ending with a final battle that left the Skull buried under the rubble of a bombed building. Because he was immediately exposed to an experimental gas there, he remained in suspended animation for decades.

Johann was eventually rescued in modern times by the terrorist organization, HYDRA. The Skull quickly subverted a cell to his own ambitions of world conquest and the death of Captain America.

The two enemies resumed their war, with Captain America, among other opponents, frustrating the Skull's schemes; not even when the Skull possessed the reality-altering Cosmic Cube could he claim victory. At one point, the Skull's health failing, he had Nazi geneticist Arnim Zola make him into an imitation of the Captain's civilian identity, Steve Rogers, using cloned tissue from Captain America's body.

Under the alias of Mr. Smith, the Red Skull had Douglas Rockwell, the head of the President's Commission on Superhuman Activities, arranged for the Taskmaster to train John Walker to become the next Captain America in order to disgrace the image of Captain America. After Taskmaster successfully trained Walker to be the next Captain America, the Red Skull had it arranged for the Taskmaster to escape from the Commission's detention center so he could continue training lackeys for him. Once Taskmaster's escape was arranged, the Red Skull hired Taskmaster to train sparring partners for him in order to get his newly cloned body of Captain America in physical fighting shape for a confrontation with The Captain (Captain America, Steve Rogers) and Captain America (John Walker). It is also possible that Taskmaster even trained the Red Skull himself.

The Skull then tried unsuccessfully to use Walker to kill Rogers. When Rogers defeated Walker, the Skull appeared to tell Rogers that he was masterminding multiple concurrent schemes rather than focusing on one grand scheme, and that he would kill Rogers at a time of his own choosing. Rogers, disturbed by this mystery man with Rogers' face claiming to be his dead archenemy, noted that the Skull was not inhaling from the cigarette he had in his mouth. The cigarette turned out to be a lethal dose of the Skull's favorite poison, the Dust of Death, intended for Rogers, but the trap backfired against Schmidt when Walker suddenly hit him from behind with his shield. As a result, Schmidt suffered the facial disfigurement attributed to the Dust, yet survived due to years of exposure to low doses.

After this, the Skull was attacked by the mutant terrorist Magneto, a Jewish Holocaust survivor who wanted to punish him for his involvement in Hitler's regime. Magneto buried him alive with enough water for a few months. The Skull remained there until he was rescued by his henchman Crossbones.

Red Skull had over control multiple criminal organizations, including the Watchdogs, a group of right-wing militiamen, and Scourge of the Underworld, an organization devoted to murdering super villains. The Skull is usually ignored by other villains because of his Nazi background, proposed an alliance with the Kingpin to bring a new designer drug to New York but the Kingpin refused to form an alliance with a Nazi. He then defeated the Skull in hand to hand combat, sparing his life on the condition he never come near the Kingpin's territory again. Fellow Nazi Baron Wolfgang von Strucker, leader of the terrorist organization, Hydra, after the Skull's agents allow Strucker to be reborn, gratefully allowed the Skull the use of HYDRA's resources.

Recently, Red Skull manipulated his way into the position of Secretary of State as Dell Rusk to develop a biological weapon he tested at Mount Rushmore, only to be assassinated by the Winter Soldier, under orders from the former Soviet general Aleksander Lukin, who wanted to possess the Cosmic Cube. When the Skull was shot, he was on the phone with Lukin and was holding the Cosmic Cube. He attempted to switch bodies with Lukin to survive, but with the cube being weak and him dying, it didn't completely work, and instead the Skull only managed to transfer his mind into Lukin's body; now the two enemies are trapped together.