The movie starts with The Invaders in a press release, explaining how they were sent forward in time and didn't really die. It pans out to show a group of children watching it - Alex Wilder, Nico Minoru, Chase Stein, Karolina Dean, Molly Hayes, and Gertrude Yorkes. Geoffrey Wilder, father of Alex, tells them that their parents will be back in an hour and not to fight. Almost immediately after he leaves, Chase huffs, standing up and announcing that they should do something less boring. Alex shushes him, but Chase begins to search the room anyway, opening the closet and finding a trapdoor leading to a tunnel. When he calls them over, they all follow and climb up to a vantage point with him. There, they see their parents performing a sacrificial ritual with a young girl named Destiny. Before they can carry it out, Molly slams her fist against the glass. This shatters it completely.
The group of children flee outside, the parents giving chase. On the way, Chase questions how Molly smashed a window open, to which she responds that she's a mutant with superstrength powers and her parents make her hide it. They reach a shed where they try and hide, Karolina beginning to question Molly on these powers - including how they never previously found out she had them, to which she replies that they were normally supressed unless she got particularly emotional. Meanwhile, Chase and Gert look around the shed, the latter screaming when a dinosaur dashed out at her. However, it was docile to her, nuzzling her hand as if it were a pet. The scream alerts their parents to their location, and they corner them inside the shed.
Geoffrey shouted that they were never meant to see that, and that it was for their own good. Molly, Gertrude, and the dinosaur step forward to protect their friends, but when Molly's parents step forward, she can't bring herself to hit them. Nico's mother, meanwhile, shouts "cuffs" at the dinosaur to chain it's feet and jaw together. Nico dashes forward with a pair of gloves she found, but her mother attempts to stab her with her staff. However, it is simply absorbed by Nico's body, confusing both parties. Gertrude's father slashes at both Nico and Karolina, cutting Nico's upper arm and slashing Karolina's bangle in a narrow miss. At that moment, the staff re-emerges from Nico's chest and Karolina begins to glow with colour. While they battle their parents, Nico discovering she can create spells with her new staff, they still fail and Chase manages to rescue them by finding a button that summons a giant robot. It knocks down the side of the shed and he prompts the team in, Nico summoning an iron gate to protect them long enough from their parents to escape.
They begin to explore what happened after taking off, one by one. Karolina explains that she believed she had a penicillin allergy, Gertrude discovers that she has a mental link with the dinosaur (now named Old Lace), Nico has no idea how she got the staff, and Alex and Chase express disappointment in their lack of powers. Alex presents a book labelled the 'Abstract', and informs Karolina that she is a 'Majesdian' - not human at all, but an alien. It also states that Nico's staff is named the Staff Of One, and it was created by a godly alien race called the Gibborim. He also tells them of their parent's reasons for sacrifice - they are a cult named the Pride, who are expecting to rule over Earth once the Pride have wiped it of all unworthy life. It turns out that they had decided to give the power to their children instead. They also rule over the city of Los Angeles as long as they make one sacrifice each year.
The group decides to turn on a television to see if they have made the news yet, and sure enough, there is a bulletin with a teary-eyed Geoffrey Wilder begging for his children. It goes on to report an alien ship crash, identified as a 'Skrull' vessel. They agree to go there and the Leapfrog lands near the crash. They agree to assume the role of heroes - Nico becomes Sister Grimm, Karolina becomes Lucy In The Sky, Gertrude becomes Arsenic, Chase becomes Talkback, and Molly becomes Princess Powerful. Alex decides the idea is stupid, but after Molly begs, he reluctantly names them the Runaways. They enter the crash site stealthily, coming across the sole survivor, Xavin. Separated from his family with no way back, he asks to join the Runaways and the team accept. Back on the Leapfrog, Xavin thanks them for taking him in, and explains that he is a Super Skrull, imbued with the powers of the Fantastic Four.
Soon after, The Runaways attempt to clear their name and rid of the bulletin by going public, with superhero pseudonyms. They face off against a superpowered group, The Wrecking Crew, who are introducing their newest member - Excavator, son of Piledriver. They beat them in combat easily, but when the cops show up, they still attempt to arrest them. Nico first tries to cast a "cuffs" spell to have them handcuff themselves, but it instead summons a frog. Realising she can only use a spell once, she instead tries "handcuffs" and finds it works this time. They escape before reinforcements can show up and head back to the Leapfrog.
They figure out that their parents have corrupted the cops, and Alex proposes they they strike directly. He claims to know their location, which raises suspicions as to how he found it (after Nico looking in the Abstract and finding nothing), they keep a close eye on him as they follow his instructions to get to them. They end up in a cave, Nico casting an illuminate spell, and see their parents facing them. Alex grabs the Staff Of One and uses it to first pull the fistigons over to him, then place the Runaways in an indestructable cell. He explains that he was working for their parents the whole time, and Geoffrey laughs down at them. Chase grins back and pushes a button, summoning the Leapfrog which crashes through the roof and knocks everyone down.
The Staff Of One lands near Molly's cell, who uses her super strength to slide it down to Nico easily, who in turn uses it to free them. Alex attempts to hit her with his fistigons, but Molly tackles him down and Chase takes them back. Gert, Old Lace, and Karolina fend off the recovered parents during this time, long enough for Nico to shout "cave in". The roof starts crumbling as the gang fights past their parents to get to the Leapfrog. Alex attempts to convince them that he should be allowed on, but Nico simply teleports him to a jail cell. The Leapfrog takes off and the roof collapses, seemingly killing all the parents. Nico hugs a crying Molly, while Chase, Karolina, Gert, Xavin, and Old Lace look on in sorrow.
The next day, they relocate to a hostel underneath the La Brea Tar Pits and watch television. Their names have been cleared, and the rubble has been searched - with no casualties found. The group begin to worry, but Chase refuses this notion - they're the strongest team in the world and if their parents return, they can take them.
In a post-credits scene, a Swiss girl in early 20th Century America sits over moss in an alley, mumbling to it. She raises her hand up to the moss, and as if by magic, it begins to spread over the wall completely. She states, "there you go, friend," and walks out of the alley.