In an alternate universe, the Joker tricks Superman into killing his pregnant wife Lois Lane, which detonates a nuclear weapon that destroys Metropolis and kills millions. Driven over the edge, Superman kills the Joker and over time murders more criminals, causing him to grow more corrupt and ultimately become a ruthless dictator.

Convincing most heroes and several villains to join his cause, he forms the One Earth Regime and rules over Earth as High Councillor, while Batman establishes the Insurgency to oppose his tyrannical regime. Over the next five years, a war breaks out between the two factions, ultimately leaving the Justice League disbanded. In a parallel universe, the Joker, with resources from Lex Luthor, also plans to nuke Metropolis. The Justice League battle Luthor's band of villains, with Batman defeating Deathstroke, Bane, and Luthor, before attempting to stop the Joker.

As the Joker prepares to trigger the nuke, he, Batman, Wonder Woman, Aquaman, Green Arrow, and Green Lantern are suddenly transported into the Insurgency's universe. Batman and the Joker are separated from the others and found by Regime forces, while Green Lantern heads to Ferris Aircraft to charge his power ring, encountering Cyborg and Raven, who are torturing Deathstroke. He defeats them, as well as Sinestro and his own Yellow Lantern counterpart, and frees Deathstroke.

Meanwhile, Aquaman travels to Atlantis to find that his counterpart is meeting with ambassadors Flash and Shazam to have Atlantis join the Regime, and defeats them, before Ares, who is weakened by the lack of violence in this world, appears and takes him back to the other heroes. In Gotham City, the prime heroes meet Insurgency Batman and Lex Luthor, who in this universe is Superman's best friend and an Insurgent mole.

They provide them with nanotech pills derived from Kryptonian DNA that empower regular humans, and explain why they transported them here: to help acquire a kryptonite weapon, for which the DNA samples of all core Justice League members are required in order to be accessed. Elsewhere, prime Batman is spotted by Hawkgirl and Yellow Lantern and captured, while the Joker encounters Harley Quinn, who is allied with the Insurgency and founded the "Joker Clan" in his memor.

After helping the Joker Clan fight off a Regime attack led by Hawkgirl and Nightwing at Arkham Asylum and locking up the Joker, the Insurgents sneak into Wayne Manor to retrieve the kryptonite weapon from the Batcave, defeating Solomon Grundy, Killer Frost, Black Adam and Regime Wonder Woman. In the prime universe, Superman, the Flash and Cyborg are attempting to recover their comrades, but accidentally send the latter into the Insurgency's universe, where he joins the Insurgency and works with Deathstroke to take control of the Regime Watchtower's teleporter.

Meanwhile, with Superman publicly announcing his intentions to execute prime Batman, the Insurgents stage a break-in at Stryker's Island to rescue him. Green Lantern, Wonder Woman and Aquaman, who is commanding an army of sea creatures, launch an attack on the Regime forces as a distraction for Insurgency Batman and Green Arrow to free prime Batman, defeating Catwoman, Nightwing, Raven and Yellow Lantern in the process. Superman abandons the fight upon realising the Insurgency took over the Watchtower and attempts to destroy it, but Deathstroke sets it to explode and he and Cyborg evacuate before the explosion sends Superman crashing back to Earth.

With Superman weakened, Luthor makes his way towards him, but is attacked by the Joker, who was released by Harley. When the Joker threatens to kill Harley, Luthor defeats him and fights his way to Superman, while Harley realizes the Joker doesn't truly love her. Before Luthor can kill Superman,, allowing Superman to execute him. Now aware of humanity's determination to depose him, Superman decides to destroy Gotham and Metropolis to demonstrate the chaos that would arise in his absence and invade the prime heroes' universe as punishment for interfering.

When Shazam protests, Superman murders him, causing Flash to defect and fight his way to the Insurgency's base to inform them of Superman's plan. While the Regime discovers and attacks the Insurgency's base, Ares teleports Wonder Woman her to Themyscira to convince the Amazons, who were ordered by Superman to attack Metropolis, to defect to the Insurgency, which she does, after defeating Raven and her Regime counterpart.

Meanwhile, prime Batman convinces his counterpart to bring prime Superman here to help. As an open war between the Regime and Insurgency erupts in Gotham and Metropolis, prime Superman defeats Black Adam, Sinestro, Aquaman and Doomsday, and convices Yellow Lantern to surrender, before engaging his counterpart in a final battle at the Fortress of Solitude.