Wary of the disaster that had befallen Krypton, Superman created an alternate reality that was meant to serve as a refuge for the citizens of Earth in case of such a calamity. However, he eventually came to realize that he no right to interfere with the destiny of the Earth in such a manner, and abandoned the reality inside the Phantom Zone, subsequently erasing his own memory of having created it.
While circling over Metropolis and keeping a watch on crime, Superman hears a cry for help from outer space and rushes to the rescue of his friend Kyle Rayner. When he returns to Earth, however, he finds that a million of its denizens have mysteriously disappeared, leaving no trace (an event that the media dubs "The Vanishing") . Lois is one of these people, and Superman struggles to overcome his guilt over not being able to save her or any of the others.
Attempting to cope with his guilt, Superman visits Daniel Leone, a priest suffering from cancer, in a series of confessionals that tell the story in media res. He comes to trust Leone and tells him how he traced the source of The Vanishing to a unnamed Middle Eastern country. Flying into a war zone, he quickly eliminates all the weapons from one side, and goes to face General Nox, a military leader attempting a coup d'etat in the country. Nox refuses to back away and unleashes a cybernetic minion called Equus, whose claws were sharp enough to cut Superman's skin. In the ensuing fight, Equus is injured and activates the Vanishing Device, which vanishes himself, Nox and a further 300,000 inhabitants of Earth.
With the Vanishing Device secured, Superman and Leone fly to the Fortress Of Solitude, where they attempt to reverse-engineer the device in the hope of vanishing Superman to wherever the missing people went so he can attempt a rescue. Before they can carry out the scheme, however, they are confronted by Wonder Woman, who refuses to let them proceed. She argues that Superman has no idea where the device might lead, which makes his task a potential suicide mission. Superman refuses to listen to her and the two come to blows. Just then, a mysterious mercenary named Mr. Orr enters the Fortress. He tells the heroes and Leone that he works for a group of individuals so powerful that "80% of the world's population work for them in one way or another". In the midst of the fight, Superman tells Diana that the Fortress is set to self-destruct, and she can either keep fighting him or save Orr and Leone. She flies them away to safety, while Superman activates the Vanishing Device. It transports him to Metropia, the alternate reality he had abandoned in the Phantom Zone.
In Metropia, Lois and Clark are reunited. It is revealed that Zod was behind the first Vanishing, as he intended to create an empire for himself in Metropia. Equus is also working for him now. Superman attacks the duo and succeeds in defeating them after a long battle. He sends all the victims of The Vanishing back to Earth and initiates the permanent destruction of Metropia. In the dying reality's last moments, Superman tries to save Zod, but Zod refuses to accept help from him.
In the background of these events, it is revealed that Orr and Leone have met in the recent past. Orr knew about Leone's cancer and told him he had a cure for it. The cure turns out to be a mutating agent that transforms Leone into Pilate, an enhanced version of Equus. Leone begs Superman to put him out of his misery, but Superman refuses, horrified at the request. Just then, Superman is attacked by the released Equus. Leone lunges at the beast and drags him down to a fiery nova, where they both disappear.
In the aftermath of the rescue, Superman begins the construction of a new Fortress in a rainforest. He thinks about all he has saved over the years, and wonders who will save him when the time comes.