Having stopped Rex Dangervest, reversed Armamageddon, and merged Apocalypseburg and the Systar System to make Syspocalypstar, Emmet's dream house is rebuilt, and Lucy gifts him an original album of "Everything Is Awesome", revealing that she co-originated the song, much to Emmet's shock.
Five years later, Emmet and Lucy, who had recently been married, are hailed as heroes of Syspocalypstar by the Syspocalypstarians. They now run a business making everything in the new society awesome, along with their unicorn-cat friend Princess Unikitty, and new friends Prince Puppycorn, Dr. Fox, Hawkodile, Richard, Master Frown, and Brock. Benny now works with his Space Squad—Kenny, Lenny, and Jenny. Batman, along with Batgirl, Robin, and Alfred Pennyworth, now lives with Queen Watevra Wa’Nabi. MetalBeard still lives the pirate life. Emmet and Lucy talk about having kids. Emmet thinks that they would have three children, either it will be three sons or three daughters. Meanwhile, in New York City, Powerpuff Girls Blossom, Bubbles, and Buttercup spy on a new evil lair called Fisk Industries, run by Kingpin (Wilson Fisk), who is fed up about why the Spider-Gang stopped him from getting back Vanessa and Richard Fisk using the Super Collider. He threatens to destroy the LEGO universe by shooting gigantic boulders from a newly invented Super Weapon to force its inhabitants to evacuate. The Powerpuff Girls manage to send the Syspocalypstarians several notes about them coming to Syspocalypstar as “emergency newcomers”.
Back at Syspocalypstar, Lucy, Unikitty, Puppycorn, Dr. Fox, Hawkodile, Richard, Master Frown, and Brock force Emmet to join them in a speed dating activity where Emmet meets fourth Powerpuff Girl Blisstina Francesca Francia Mariam Alicia Utonium who deems him incompatible. Blossom, Bubbles, and Buttercup meet Emmet at his house and convince him to assemble a great army of Master Builders to build an alliance with the Girls. They recruit Lucy, Unikitty, Puppycorn, Dr. Fox, Hawkodile, Richard, Master Frown, Brock, Benny, Kenny, Lenny, Jenny, MetalBeard, Queen Watevra Wa’Nabi, Batman, Robin, Batgirl, Alfred, Superman, Green Lantern, the Wonder Women, Cyborg, Flash, Aquaman, Shazam, Bliss, Sweet Mayhem, Ice Cream Cone, Chad, Amber, Zebe, the Duplo aliens, Chocolate Bar, Balthazar, Celeste, Susan, Banarnar, Flaminga, Eight, Archimedes, Lloyd, Kai, Jay, Zane, Cole, Nya, Wu, Koko, Garmadon, Iron Man, Hulk, Thor, Loki, Captain America, Black Widow, Hawkeye, Spider-Man, Spider-Gwen, Peni Parker, Spider-Ham, Spider-Man Noir, Miles Morales, Ant-Man, the Wasp, Iron Fist, Black Panther, Deadpool, Wolverine, War Machine, Star Lord, Rocket, Groot, Drax, Gamora, Mantis, Nebula, Winter Soldier, Scarlet Witch, Vision, Falcon, Magneto, Storm, Pepper Potts, Colossus, Captain Marvel, Doctor Strange, Nick Fury, and Maria Hill. A secret meeting the crown of the Statue of Liberty is interrupted by a school dance performed by the Loud kids—Lori, Leni, Luna, Luan, Lynn, Lincoln, Lucy, Lana, Lola, Lisa, and Lily—in front of a gazebo in Syspocalypstar National Park. The dance is led by an eagle named Glenn, with the Birds, Hatchlings, Pigs, Minions, and Eagles watching. Emmet interrupts the dance and announces their plan to stop the Super Weapon to everyone.
As the team prepare to travel to New York City by ship, Emmet assures the civilians that they do not need to evacuate. Once there, Nick Fury brings in 50 4x4s and they drive all the way to Fisk Industries. Garmadon confesses that he and Koko broke up. Emmet insists on fighting alone but Lucy, Blossom, Bubbles, Buttercup, Bliss, Unikitty, Puppycorn, Hawkodile, Dr. Fox, Richard, Master Frown, and Brock follow them instead. They intrude the base from the mouth of the weapon only to be captured by the guards. The other team members disguise themselves as Riot and grab a key card to get into the base. Their disguise rips apart, but not before they drive the guards to a breakdance battle, allowing them to escape.
Back in Syspocalypstar, the Loud kids (except Lincoln and Lola) set up the hot air balloon. Princess of Mewni Star Butterfly tells its civilians that the kids will be on the lookout of the giant boulders that come from the Super Weapon. They get into the hot air balloon, and they fly off. They think of a plan to know where the boulders are coming from.
As Emmet, Lucy, Blossom, Bubbles, Buttercup, Bliss, Unikitty, Puppycorn, Hawkodile, Dr. Fox, Richard, Master Frown, and Brock are all tied up in ropes, Kingpin tells them his plan to fire giant boulders not just at Syspocalypstar, Gotham City, and Ninjago City, but also at Middle Zealand and the Old West. He then demonstrates the power of his newly upgraded cannon in a show of force.
Elsewhere, the Loud kids suddenly see the boulders being fired at Syspocalypstar, Gotham City, and Ninjago City. All of Syspocalypstar's civilians run around panicking, but snowman Olaf leads the Syspocalypstarians to Elsa's Ice Palace, which is a place for safety, with the help of Marshmallow and the Snowgies. In Gotham City, Mayor McCaskill tells all of Gotham's civilians as well as its criminals to evacuate and head for BlĂĽdhaven. In Ninjago City, the Mayor of Ninjago tells the city's civilians to head safely to the Temple of Fragile Foundations where the Secret Ninja Force tried to find the Ultimate Ultimate Weapon.
In the aftermath, Star Butterfly climbs from the ruins. Minions Otto, Kevin, Stuart, and Bob, Owen Grady, velociraptors Blue, Ripley, Connor, The Other One, Lincoln Loud, Lola Loud, and unicorn Donny, tell her that the boulders that came from the Super Weapon attacked them. Feeling guilty about the destruction of Syspocalypstar, Star gathers together the rescue team to go help the Master Builder-Powerpuff Girl Alliance, Master-Building another flying vehicle, now with an internal motor similar to Ultrakatty's. Once they do, they fly over to New York, and land near the base. When they get near the guards, they beat them up. They meet up with the team, and ask where Emmet and his friends are. Benny points to the exact same room where they had been tied up in ropes.
Emmet, who regrets not telling the citizens of Syspocalypstar to evacuate, admits his selfish desire to be liked by everyone to his friends, who comfort him. Blossom also tells Emmet about what happened to their Professor when the Super Weapon attacked Townsville. The Powerpuff Girls free them all using one of Dr. Fox’s inventions, reuniting with the now extended team. Emmet gives up his leadership to the Girls, who establish a plan to destroy the weapon. The Powerpuff Girls, Emmet, and Lucy put themselves into a boulder (in which Blossom turns it into glass), and they roll it down the long, spiraling ammunition of Kingpin's Super Weapon, with their allies working to sever the track by reaching and pulling a particular swing so that the six would fly off and crush the cannon, but the plan fails and the entire team are confronted by all the guards and Marvel Villains, giving Kingpin a chance to fire the weapon.
Suddenly, Trolls Poppy, Branch, Biggie, Cooper, Guy Diamond, and Tiny Diamond arrive to stop and confront Kingpin and his crew, and he reveals to them that Thanos was working for him after the incident about why he wiped out half of the universe. While Kingpin is distracted, Dr. Fox tells Batman to tie up the weapon using some thread, which catches and decelerates the boulders after Kingpin fires them. As the thread breaks, the Loud kids and the other Minions (who used their plane to escape the prison) passing by New York City, grasp it. The boulders slide back into the weapon, destroying the whole base. Everyone escapes, and MetalBeard survives by protecting the Powerpuff Girls from being burned by transforming into his heavy metal motor trike. Garmadon proposes to Koko and promises not to let her go again.
Afterwards, Emmet and his friends, along with the civilians of Syspocalypstar, Gotham City, Ninjago City, and New York City celebrate their victory, and merge the four cities as well as Unikingdom, Frown Town, Wakanda, Asgard, the Old West, Middle Zealand, 1980s Space Era, and Action Forest to create the city of New Bricksburg, with the Statue of Liberty rising up again and returning to its regular color. Garmadon and Koko get married at Warner Bros. Studios, with Emmet as the chief witness, Dr. Fox and Star Butterfly as the flower girls, and Young Gru as the man of honor. Everyone praises Emmet and Lucy for saving the LEGO Universe, but Emmet credits the Powerpuff Girls and the team for doing so, unveiling a Mount Rushmore-style monument as well as a statue of the late Vitruvius to them, and to their surprise, being even more beloved for his honesty and selflessness. The civilians of New Bricksburg have a huge party with Aqua’s “Barbie Girl” playing, while Emmet and Lucy take the Powerpuff Girls to their house, now located next to Unikitty’s Castle to reveal their new room. Emmet and Lucy agree to stay one big happy family no matter what.
In a mid-credits scene, in the same Warner Bros. studio, after the Master Builders end their party (which actually took place near the cinema), Young Gru, the Minions' boss, asks them if they could come see the premiere of Scoob!, and that Emmet and the team are waiting at the cinema lobby. The Minions agree as they enter the theater. Meanwhile, Mojo Jojo and Princess Morbucks arrive, wondering what they missed.
In a post-credits scene, in a cut-down scene of The Powerpuff Girls Movie 2: Generations, Blossom, Bubbles, and Buttercup discover that the portal had been malfunctioning, as it brings in the 1998 Powerpuff Girls, who tell them that nothing is what is seems in all the dimensions, and that the Giant Fishballoon is coming back to destroy them. The Girls agree to help their past selves by telling the Professor what happened, as the post-credits scene ends.