The main miniseries debuted in October 2005, and each issue was released with two variant covers: one by Pérez and one by Jim Lee and Sandra Hope.

DC Comics executive editor Dan DiDio stated that Infinite Crisis was being hinted at in various stories for two years prior to its launch, starting with the "death" of Donna Troy.

The story begins in the wake of the four lead-in limited series, with Superman, Wonder Woman, and Batman feuding, the JLA Watchtower destroyed, and the heroes of the world all facing a variety of menaces.

Believing Lois' health will improve on her native world, he hopes to replace the current Earth with Earth-Two, which he considers perfect.

[7] Alexander reveals to Power Girl that he and Superboy-Prime had been leaving their "paradise" for some time, manipulating events to help create an inter-dimensional tuning fork.

When Earth-Two Lois dies of old age, an aggrieved Kal-L and the younger Post-Crisis Superman Kal-El fight until Wonder Woman separates them.

[10][11][12] Bart Allen (wearing Barry Allen's costume and aged to adulthood) emerges from the Speed Force, warning that he and the other speedsters were unable to hold Superboy-Prime, who returns wearing Anti-Monitor inspired armor that stores yellow sun radiation to empower him, making him even stronger.

When a horde of supervillains attack Metropolis,[15] heroes, current and retired, fly off to the rescue, and they are joined by the National Guard.

The battle results in multiple deaths on both sides, including many by Superboy-Prime himself, who kills villains and heroes alike.

During the battle, Superboy-Prime takes off to destroy Oa, planning to collapse the Universe in a big bang event, and recreate it with himself as the only superhero.

The Supermen fly Superboy through Krypton's red sun Rao, destroying his armor and causing all three Kryptonians' powers to diminish.

Kal-El finally knocks Superboy-Prime out before succumbing to the kryptonite radiation poisoning (but saved the Corps) and the older Superman Kal-L dies of his injuries.

Back on Earth, Batman, struggling with Superboy's death and Nightwing's severe injuries sustained during the Metropolis battle, contemplates shooting Alex.

Batman plans a similar journey of self-discovery, revisiting the training of his youth, this time with Dick Grayson, now healthier, and with Tim Drake joining him.

[18] The hardcover collecting all seven issues of Infinite Crisis included changes in coloring, as well as, more significantly, alterations in dialogue, most of which relate to hints to the re-emergence of the DC Multiverse.

Ace Books, under the imprint of the Berkley Publishing Group and published by the Penguin Group, released an October 2006 novelization adaptation of the series written by Greg Cox, with an introduction by Mark Waid, and cover art designed by Georg Brewer and illustrated by Daniel Acuña.

A multiplayer online battle arena video game adaptation loosely based on the comic book series was developed by Turbine, Inc. and released in 2015.