The film (set from 1953-1960) begins with an unknown entity explaining how it has witnessed the evolution of life on Earth:
- "Like all things on this hurtling sphere, I emerged from the molten center of creation. But mine has been a unique path. Isolated, I developed attributes beyond those of lesser beings. Then the sphere was struck by a vast celestial stone. Black chunks of death filled the skies and the world became a chaotic garden of doom. Soon the sphere began to nurture new kinds of life. And there was one that stood above the rest. Its fragile shell belied its vicious nature. And in what seemed like a heartbeat, these things proliferated in both number and destructive means. Now they have harnessed the most destructive force. And I, The Centre, have concluded that the sphere must be cleansed of them."
- ―The Centre [src]
This explanation is shown being written and illustrated under the title "The Last Story" by a mysterious person who then shoots himself.
The film cuts to the end of the Korean War, where United States Air Force pilot Hal Jordan and his wingman, Kyle "Ace" Morgan, are attacked by enemy pilots not yet informed of the cease-fire. Hal is shot down in the ensuing conflict, and forced to kill a North Korean soldier after ejecting to safety. The trauma of this event leads Hal to a mental ward within a hospital for two years.
Elsewhere, at Gotham Observatory, the last survivor of the Green Martian race, J'onn J'onzz (voiced by Miguel Ferrer), is inadvertently teleported to Earth by a scientist, Dr. Saul Erdel. The shock of J'onn's appearance causes Erdel to succumb to a heart attack, though not before he apologizes for stranding the Martian. Unable to return to Mars, he disguises himself as Dr. Erdel.
The following year, Superman meets Wonder Woman in Vietnam, where she celebrates with a group of women she rescued from political rebels. The Amazon allowed them to exact their own brand of fatal justice upon their captors, which Superman is horrified to learn. He reminds Diana that the government is distrustful at best of the heroes, which has led to the Justice Society's disbanding and Hourman's death, as well as Batman's branding as a fugitive vigilante. Superman also tries to remind her that mitigating the general public's fear is why they signed loyalty oaths to the United States government. Diana, however, resolves that she must do what she feels is right. The two part at odds, and Diana later leaves America to return to Paradise Island. Superman later confides in Lois Lane about Wonder Woman and Batman, neither of whom, he says, would sacrifice their principles for each other.
In Gotham City, J'onn J'onzz has been living quietly under the guise of Dr. Erdel, while learning what he can about humans and Earth society through television. He shape-shifts into different guises during his nightly viewing, such as Groucho Marx and Bugs Bunny, before settling on the form of a film noir detective.
In Las Vegas, reporter Iris West is on assignment to interview singer Buddy Blake, at the same casino where Hal Jordan and Ace Morgan are enjoying themselves. While Iris is on the phone with her boyfriend Barry Allen , Captain Cold arrives to rob the casino. Hearing the events on the phone, Barry races to Vegas from Central City as The Flash and confronts Cold, who tells him he has hidden six cryogenic bombs around Vegas set to go off in 90 seconds. Flash zips around the city and locates five of the bombs, but deduces the sixth is a decoy, and captures Cold before he can escape by helicopter. Before being subdued, Cold is possessed by the unknown entity from the prologue, who asks Flash why he is faster than "the other lesser beings" before leaving the Rogue.
Hal and Ace leave the casino and head into the desert. Hal is unclear about their destination, which Ace keeps a surprise. Ace notices Hal has been acting differently, and Jordan confesses things haven't been the same since the war and his time in the hospital. He also admits his past hospitalization has kept him from getting a job with a top aircraft company. It's after Hal confides in Ace that the two arrive at Ferris Aircraft, where an opening as a test pilot is indeed waiting for Hal, thanks to a recommendation from his friend.
Back in Gotham, J'onn joins the Gotham City Police Department under the name John Jones, and with his integrity, cunning analytical skill, and telepathy, quickly rises to the ranks of detective in just two years. After investigating a kidnapping of a child which was later discovered to be part of a sacrificial ritual for a cult that worships something called The Centre, J'onn and his partner Slam Bradley meet Batman for the first time as he is also investigating the kidnapping. The two cops join Batman in battle against the cult, but a fire is started during the fight, rendering J'onn powerless until Slam extinguishes it. Afterward, when Batman attempts to free the boy from his bonds, the child is terrified at the sight of him. J'onn arrives to calm the boy down and then he and his partner free the child themselves. The entity which possessed Captain Cold speaks through the incapacitated cult leader, identifying itself as "The Centre" and warning of an impending judgment.
Hal Jordan begins training exercises under Col. Rick Flagg at Ferris Industries. His joking, devil-may-care attitude rubs Flagg the wrong way, but Carol Ferris is understanding and recognizes Hal's natural ability. Carol also recognizes that Hal needs to know the true nature of his training, which she soon reveals to him: the government has commissioned Ferris Aircraft to build a spacecraft capable of travel to Mars. Special agent King Faraday is assigned to oversee the project, which is in response to Dr. Erdel's contact with Mars and J'onn's arrival.
Back in Gotham, the Dark Knight reveals his knowledge of J'onn's true nature in his apartment, as he is able to find a way to shield his mind from J'onn's telepathy, and suggests that they should form an alliance as they are both investigating the cult that is rising throughout the world— cult that worships the Centre. J'onn's demonstration of kindness toward the boy led Batman to believe that he can be a trusted ally. However, he warns J'onn that should he betray him, he is fully aware of and willing to use the Martian's vulnerability to fire against him.
In Central City, The Flash defeats Gorilla Grodd (or, rather, a robotic duplicate), but is targeted by government agents, as they attempt to capture him in an effort to learn the secret of his powers. Though he narrowly escapes, the experience leads the Flash to consider retiring from his crimefighting career.
J'onn J'onzz interrogates Harry Leiter, a former Ferris employee apprehended for murder while under the influence of the Center. During the questioning, Harry lets word slip about the launch to Mars. Leiter's ramblings are confirmed when Faraday arrives to take him into custody. J'onn briefly glimpses into the agent's mind and learns the truth. After watching the Flash announce his retirement on live television, and seeing the public contemptuous response, a disheartened J'onn attempts to stow away on the rocket so that he may return home. Before leaving, he arrives in Batman's headquarters, the Batcave, revealing that he's been aware of Batman's secrets for quite some time (using his cunning detective skills instead of his telepathy), and gives him the last of his research on The Centre. J'onn reveals to Batman that he's losing faith in humanity, as he sees that there's too much hatred, ignorance, and conformity within the people around him, which made him decide to leave Earth. Batman's response is cold and brief, as he tells J'onn some people don't have the luxury of leaving Earth.
While attempting to board the ship, J'onn is seen on camera by Faraday, who confronts J'onn and fights him on the launchpad. J'onn is able to beat Faraday, but saves him from the rocket exhaust by flying him to a platform before collapsing. The rocket is damaged and malfunctions shortly after exiting the atmosphere. Hal wants to attempt a landing, but his co-pilot, Col. Rick Flagg, reveals that the rocket is loaded with weapons of mass destruction, and as such he won't risk it. After a brief struggle, Hal is ejected from the cockpit. Though he is saved by Superman, the distraction allows Flagg to detonate the rocket.
J'onn J'onzz is held as a prisoner by Faraday. Superman blasts Faraday for treating J'onn differently from him (a Kryptonian and thus also an alien), just because J'onn looks radically different. He also points out the captivity is entirely J'onn's decision because he can escape at any time using his powers.
On Paradise Island, Wonder Woman trains with Mala, and tells her of how America has changed since the war. Her training partner says the island has changed as well, and that many Amazons desire a change in leadership. Though Diana quickly fends off a challenge from her fellow Amazon, the two of them are soon beset upon by the approaching Center.
Hal Jordan is later found by Abin Sur, the Green Lantern of Sector 2814. The destruction of the rocket badly wounds him as he enters Earth's atmosphere, so he instructs his ring to find a worthy replacement. He leaves his ring with Hal, and tells him of The Centre, which he describes as a "monstrous creature" that fears humans and seeks their destruction.
In the Batcave, Superman reviews J'onn's research with Batman and meets Robin (voiced by Shane Haboucha) for the first time. Batman has altered the design of his suit so it won't frighten an innocent, but is still able to strike terror in the heart of a guilty. As they discuss the Centre, they hear Lois reporting on the attack of a giant pterodactyl at Cape Canaveral. Superman arrives at the scene and quickly defeats the creature. Almost immediately afterwards, Wonder Woman's invisible jet makes a crash landing, its cockpit smeared with blood. Before losing consciousness, Wonder Woman warns Superman that the Centre is coming.
Faraday eventually befriends J'onn who saved his life, and occasionally plays chess with him. J'onn reveals to Faraday that he decided to remain at the agent's base willingly because of the upcoming battle with The Centre, and had telepathically looked into the agent's mind during their battle at the platform. J'onn found that Faraday believes that one day the world won't be living in fear and hate. Finding that within Faraday, J'onn has renewed hope for humanity and decides to participate in the battle to save Earth. Before leaving with Faraday, J'onn adopts a new Martian/human superheroic hybrid form as the Martian Manhunter, believing it is honest to his heritage with a friendly appearance to human perception.
Following this, the Centre begins its attack in earnest at the coast of Florida, finally revealed as a massive flying island, with an army of mutated dinosaurs to guard it. The threat draws heroes such as Flash (whom Iris talks into coming out of retirement), Green Arrow, Adam Strange, the Challengers of the Unknown, and the Blackhawks, who clash with the soldiers on base. The conflict is stopped by Superman, who advocates cooperation between the two sides. He is unexpectedly seconded by Faraday, accompanied by J'onn, who agrees that the government and the heroes must work together for freedom. With that, Superman heads out to do reconnaissance on the Centre, but is swiftly and shockingly defeated.
Moved by his effort, the rest of Earth's superheroes and military forces band together to defeat the Centre. Batman interrupts a meeting between Faraday, J'onn, Will Magnus (voiced by Townsend Coleman), and the Challengers. Batman brought with him Ray Palmer, a scientist known for his work with matter reduction. When one of the Challengers argues the technology is too unreliable, destabilizing anything it shrinks, Batman replies that's exactly the point, and a plan is formed to use Palmer's reduction ray to destabilize the island. The heroes will distract the Centre with a frontal assault (while Hal and Ace fly a bombing mission into the creature), leaving Flash to quickly crisscross the island with the ray.
While the aerial assault (including Batman and Green Arrow as pilots) is nearly outmatched before the intervention of the Blackhawks, Faraday's ground forces are ambushed by a herd of rampaging mutant dinosaurs. J'onn is overwhelmed by the psychic impact from The Centre and is rescued by Faraday, who is shortly thereafter captured by a dinosaur. As he is about to be eaten by a tyrannosaurus, Faraday grabs two hand grenades and pulls the pins. The dinosaur swallows Faraday and immediately afterwards its head explodes from the grenade detonation, killing both it and Faraday. The shock of his friend's death helps J'onn shake off the Centre's hold, and he and a recovered Wonder Woman help turn the tide of the ground battle.
Hal Jordan and Ace Morgan manage to shoot their way into the core of the creature, but are disoriented at first by its hallucinogenic effects. The creature secretes a thick red fluid that jams their weapons and almost suffocates them. It is then that Hal's ring activates, relaying instructions from the Guardians of the Universe (voiced by Robin Atkin Downes) as to its use. Ace manages to detonate his payload, and is rescued by Hal – now dressed in a costume identical to Abin Sur's – just before his plane explodes.
The explosion gives the ground crew their opening as they prepare to send Flash to finish the creature. The speedster is struck by the gravity of the situation and his role in it, but J'onn reassures him that everyone will be behind him. Flash races across the ocean and leaps onto the Centre's surface, covering the entire surface on foot before leaping into the ocean. The Centre begins to shrink, but realizing its imminent destruction, it heads toward land to destroy the humans along with it. Hal realizes what he must do, and envelops the island in green energy, then tows it into space where it explodes.
The entire world celebrates the Centre's defeat. As many participants in the battle attend a ceremony, Hal celebrates the victory his own way by pursuing his lifelong dream: flying through space with the aid of his new power ring. During the celebration, Superman is revealed to be injured but still alive, saved by a man named Arthur (voiced by Alan Ritchson) who claims to be from an underwater kingdom. He and his subjects treated Superman's wounds during the battle with the Centre. Superman is reunited with Lois and the rest of the heroes, who are touted so on the front page of the Daily Planet.
This monumental victory and display of teamwork changes public opinion about superheroes, and a montage of various heroes and villains (with cameos by Black Canary, Captain Marvel, Plastic Man, Robin, Supergirl, the Teen Titans, Ra's al Ghul, Black Manta, Brainiac, Cheetah, Darkseid, Doctor Light, Doctor Sivana, Gentleman Ghost, Joker, Key, Lex Luthor, Monocle, Mr. Mxyzptlk, Harley Quinn, Riddler, Star Sapphire, Two-Face, and Ultra-Humanite) as well as the birth of the world's second generation superhero team: Justice League, set to the titular John F. Kennedy speech, is shown just before the film ends.