Two year after their battle with Mojo Jojo and Derek Sackz being sent to prison, the Powerpuff Girls still live in secret, having allowed Otto Osworth to take the credit for Jojo and Sackz's defeat. The girls watch a Townsville Knicks basketball game. As Mojo is transferred between prisons by corrections officer Wally Beatles, his Moja Clan – operating under the direction of scientist S. "ManDark" Astronomonov – attack the convoy transporting him. The Girls, tipped off to the attack by Kuki Sanban, intervene. ManDark is still able to affect Mojo's escape using a teleportation device, but Mojo is hijacked mid-teleport and winds up in another dimension. There, the alien warlord Hector Con Carne, Boskov his bear-headed cyborg and his talking stomach. Whom Con Carne gives him a Chem-X compound in exchange for his promise to find three components of a machine Con Carne sent to Earth in ages past, which will open a portal to his dimension when united.
Mojo recruits two criminals that were being transported alongside him, Ozzy "Fuzzy" Lumpkins and Harry Ian "H.I.M." Myers, and has ManDark use Con Carne's Chemical X on them to transform them into powerful half bear and lobster mutants. Kuki witnesses their transformation, and is able to steal the vial of chem-x. Pursued by the Mojas, she is rescued by Wally. In the scuffle, the vial is taken into police custody.
Bunny Utonium deduces that the chem-x could be used to turn the Powerpuff Girls into normal girls, enabling them to live normal lives among the people, but Blossom Utonium refuses and insists on keeping it a secret from the others. Bubbles Utonium overhears their conversation and tells Buttercup Utonium, leading to a fierce argument between the sisters. Furious, Buttercup recruits Bubbles, Kuki, Wally and Otto to break into the Townsville police headquarters and recover the chem-x. The Mojas arrive ahead of them and in the ensuing battle, the PowerPuff Girls' existence is revealed to the police, who react with fear and hatred. The sisters escape, but Kuki and Wally are arrested. With Mojo's forces having already recovered two of the pieces of the portal device, the Powerpuff Girls track Fuzzy Lumpkins and H.I.M. as they recover the final piece from the Brazilian rainforest. The Girls intercept their jet on its return journey via skydive, and although the battle crashes the jet, Fuzzy and HIM manage to escape with the final component.
The girls return to Townsville to watch as ManDark and Mojo complete the portal device and open the gateway to Con Carne's dimension, through which his modular war machine, the Conquodrome, begins to emerge. Mojo betrays ManDark and has his men take him away, but upon entering the Conquodrome, Con Carne betrays Mojo, freezing him and locking him away with his collection of other defeated foes. Seeing no way to combat the Conquodrome discreetly, the girls debate over taking the chem-x and becoming normals in order to fight openly.
Though Blossom agrees to do it, Buttercup shatters the vial, realizing that they must accept themselves. Otto recovers security footage that proves ManDark and Mojo's crimes and secures Kuki and Wally release, allowing them to set up a meeting between the girls and police chief Rachel T. McKenzie, where they convince her that they aren't enemies. The Powerpuff Girls then go into action, confronting Con Carne aboard the still-assembling Conquodrome. Meanwhile, Wally keeps Fuzzy and HIM busy and defeats them by capturing them inside a container with a grenade with them, while Kuki and Otto defeat Mojo's lieutenant Sedusa and take control of the portal device. The Powerpuff Girls locate the beacon around which the Conquodrome is assembling and hurl it back through the portal, taking Con Carne, Boskov and the rest of the Conquodrome with it. Kuki, Wally and Otto then shut the portal down. As he disappears, Con Carne swears he will return for revenge. In the aftermath, Sedusa, Fuzzy and HIM are taken into custody, while ManDark remains at large. The Powerpuff Girls are honored by McKenzie and the TPD, along with Kuki, Wally, Professor Utonium and Otto, but elect to keep their existence a secret from the public at large.
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Blossom Utonium: Professor, the Moja Clan are intending to break Mojo out!
Professor Utonium: If Mojo is free, is reign of terror over the city will begin again.
Blossom Utonium: Exactly!
Professor Utonium: Then there is only one question: why are you wasting time talking to your old man? Go get him!
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Mojo Jojo: We meet again, Girls!
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Hector Con Corne: [to Mojo] I know what you're feeling right now, you're thinking of all the ways you'd like to kill me. But that would require out-thinking me. And no one, nothing is smarter than HECTOR CON CARNE! [slaps Mojo] Oh, I'm sorry, did I get a little spine mucus in your eye?
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Hector Con Corne: Boskov place me back in! [Boskov push him into his top head slowly] Push me in, you stupid bear! [Boskov punches him into its head] You idiot!
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Buttercup Utonium: Every minute we stay here, Mojo gets stronger and Bubbles gets more annoying!
Bunny Utonium: We're training! As soon as our bedtime is over, it's PowerPuff time!
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Mojo Jojo: [to Fuzzy and HIM] I'm looking for errand boys.
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Mojo Jojo: [holds up CX mutagen] This will help us build an army.
ManDark Astronomonov: [mutates Fuzzy and HIM] This is gonna be good! [Fuzzy and HIM see how they've mutated]
Fuzzy Lumpkins: You're a man-lobster!
H.I.M.: And you're a... I don't know what you are!
Fuzzy Lumpkins: [sees his reflection] Huh, I'm a monkey-thingy?
ManDark Astronomonov: You're a bear.
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Kuki Sanban: What's your name?
Wally Beatles: Wally Beatles.
Kuki Sanban: [smiles] Hey.
[Bubbles appears]
Bubbles Utonium: One question... so are you two like a thing?
Wally Beatles: [on the Powerpuff Girls] Who are these girls?
Kuki Sanban: They're my friends.
Bubbles Utonium: This is Blossom! She's our fearless leader! Buttercup's like a cuddly teddy bear... if big cuddly teddy bears were incredibly violent. Bunny, she's a technical genius. And I'm Bubbles! I'm a triple threat: brains, brawn and a dazzling personality!
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Bubbles Utonium: [chuckles at Fuzzy] Dude, bringing back the pink fur! Good for you!
Fuzzy Lumpkins: Oh ho ho, you all gots jokes, huh? Well, let's see how funny you are after we bash your heads! [Fuzzy and HIM attack]
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[the Powerpuff Girls, Fuzzy and HIM float down a river]
H.I.M.: Bye, Girls!
Bubbles Utonium: That's nice of them to say goodbye...
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H.I.M.: Heads up! [the Powerpuff Girls go over a waterfall screaming]
Fuzzy Lumpkins: Girls are out, lobster and bear are in!
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[a vortex opens in the sky] Blossom Utonium: What's happening out there, Bunny?
Bunny Utonium: I don't know, but it doesn't look good...
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Mojo Jojo: Once the Conquodrome is assembled, we can rule the planet.
Hector Con Corne: I'm sorry, we? WE will rule? Ha-ha!
Mojo Jojo: We were a team...
Hector Con Corne: "We are a team..." Teams are for the weak! Family is for the scared! The Earth is MY "toy", and I do not like to share!
Mojo Jojo: You betrayed me!
Hector Con Corne: Actually, I barely even thought about you! [Mojo draws his blades, but Hector freezes him and stores him inside the Conquodrome] Back to the "toy chest", with the rest of the "things I've broken"! Silly little earthling! Time for a new game! Look out, Earth, it's "playtime"!
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Fuzzy Lumpkins: We gotta keep our eyes out for intruders!
H.I.M.: Well, what do intruders look like?
Fuzzy Lumpkins: Anybody that's not a big bear or a big lobster!
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Bubbles Utonium: [taps Con Carne's glass dome] I was expecting way worse. [Con Carne pops out] It's look like a brain with eyes!
Hector Con Corne: You know, I'm looking forward to enslaving you!
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[Blossom chops off the Boskov's cyborg arm]
Hector Con Carne: You think I didn't plan for this? [summons a replacement arm and new weapons]
Bubbles Utonium: Girls, he's literally re-arming!
Hector Con Corne: Stupid females!
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Hector Con Corne: [grabs Bubbles] Come here, little girl! Let Boskov give you a BEAR hug, GOODBYE! [puts Bubbles in a bear hug]
Buttercup Utonium: Nobody!
Blossom Utonium: Messes!
Bunny Utonium: With Bubbles! [all three take down Boskov and Con Carne]
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Hector Con Carne: [he is teleported away from Earth] I'll be back, Powerpuff Girls, but a thousand times stronger!
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Rachel T. McKenzie: I think you should give people more credit. They'll accept you now.
Buttercup Utonium: You're probably right... but I think we'll stick with the arrangement we had.
Blossom Utonium: You ever need us, Kuki knows where to find us.
Rachel T. McKenzie: Really? You could live a normal life, like the rest of us.
Buttercup Utonium: Normal... what fun is that?