Ryan, Winnie the Pooh, Ash Ketchum, Littlefoot, Spongebob, Skipper, The Fantasy Adventure Team, Bobby, Cindy, Greg, Marcia, Peter, Jan, Oliver, Millicent, DJ, Stephanie, Michelle, Alex, Nicky, Malcolm, Mallory, Reese, Renee, Dewey, Daisy, Emily Yeung, Daniel Cook, the Jungle Adventure Crew, the Madagascar Crew, the cubs, Aladar, Taran, Jesse, Mikey, Bloom, and the rest of the characters meet The Heffley family attend a party at a roller rink, where Greg (Zachary Gordon) reunites with Rowley (Robert Capron), Fregley (Grayson Russell) and Chirag (Karan Brar). Greg meets a new girl at school, Holly Hills (Peyton List), and then talks about his summer. Rodrick (Devon Bostick) starts persuading violent teenagers to enter the rink. Their mom, Susan (Rachael Harris) and dad, Frank (Steve Zahn) humiliate him by speaking to him on the DJ system and carrying him off the rink (although his dad apologizes, having been equally humiliated). Afterwards, Mom has noticed that the boys haven't been getting along so she devises "Mom Bucks", play money she will pay them if they spend time together and can then trade in for one real dollar, but this makes things worse. Meanwhile, Greg and Rowley try to make a funny YouTube video of Rowley lip-syncing to the song "Tik Tok by Kesha" while wearing underwear on his head. Unfortunately, it proves to be awful, getting only 4 views. When a talent show is advertised on TV, the brothers see this as a big opportunity – Rowley suggests that he and Greg perform magic tricks, but Greg rejects the idea while Rodrick sees this as his band's big break. On Sunday, the Heffley family goes to church but Greg is extremely reluctant to go inside, as a melted chocolate bar, intentionally placed on his seat by Manny, has stained his trousers. Greg's mom uses her coat to cover up the stain, but the cover-up backfires when Rodrick exposes Greg's pants. The boys ultimately end up in a scuffle on the floor and as punishment, they are to spend a whole weekend together to bond while their parents leave to go to a hotel. Against his parents' orders, Rodrick has a party at the house and locks Greg in the basement. Rowley comes to save Greg, but Rodrick locks him in the basement as well, until a call from their mother results in Rodrick letting the two out in return for their silence on the matter. The next day, the two get a call from their mom, informing them that they are returning early from their trip. The house is trashed, and the boys have to clean it up and erase all evidence of the party before their parents come home. When they see that one of the people wrote "Rodrick Rules" on the bathroom door, they replace the door with a different one. Afterwards, Greg notices that the new door does not have a lock while the old one did. Rodrick tells Greg to "deny, deny, deny" and he tells the same to Rowley. Chirag comes home from a trip to India and makes fun of Greg at school for not hanging out with Holly when Greg said that when Chirag comes back from India she will be hanging out with Greg. In revenge, he starts the "Invisible Chirag" joke when everyone pretends they cannot see him. Rowley came over for a sleepover, for a night. Next, Bill Walter meets Rodrick, for supper whilst Dad takes an instant dislike to Bill when he finds out he still lives with his parents and persuades Greg and Rowley to live a rockstar lifestyle. Greg chooses a horror movie for the sleepover which terrifies Rowley and Greg. Rowley left Greg's house, after Greg said, "sorry" to Rowley. Mom notices that the lock on the bathroom door is missing and interrogates Greg and Rodrick. Greg confesses, but in order to prevent Rodrick from getting angry at him, he says the party was only a band rehearsal, and the two escape punishment. Rodrick thinks that Greg denied everything, and the brothers become friends, with Rodrick teaching Greg about his secrets to an easy life. Rodrick gives Greg his "100 years ago" assignment which he failed but Greg thought he got a good grade as it is revealed that Dad had helped Rodrick with every homework assignment that he did. The Invisible Chirag joke was still going on and at lunch that day Chirag almost ended it when he nearly blackmailed Rowley into having a corn dog if he said he could see Chirag but Greg told everyone that there was a floating corn dog and he ate it. After lunch, the class presents their "100 years ago" assignments but the teacher humiliates Greg by making him read Rodrick's assignment which included cavemen and dinosaurs. The next day, in an attempt to win Holly, Greg writes her a note and asks Rowley to pass it to Holly, he does but she passes it to Fregley and he accidentally passes it to Patty Farrell. The day after that, Greg finds a note from Holly Hills in his locker telling him to meet her in the art room. Instead, he finds Chirag, who has dressed up as Holly to trick Greg as revenge for his "invisible Chirag" joke. In the hallway, Holly passes by and greets Greg as "Fregley", which upsets Greg. That night, Rodrick takes Greg out for the night. They end up having fun, eating hot dogs, drinking slushees and pranking people with fake vomit. However, one prank goes too far when Coach Malone (Andrew McNee) chases them into the mall. The boys return home, only to discover that their father has come across photos of the party that they threw while their parents were gone. Greg is grounded for two weeks with no video games, and Rodrick is only allowed to drive to and from school for a month and is not allowed to participate in the talent show. Greg tries to apologize but Rodrick, realizing that Greg had lied to him, tells him that they are no longer friends and they return to being rivals. Later, they have to spend the weekend at Grampa's retirement community. They find it extremely boring, particularly because Grampa only watches the lobby on the security channel on TV and they have to play a game called "Gutbusters" when the aim is to try not to laugh at jokes which are not funny. Greg finds Holly there and she apologises for calling him Fregley and they become friends. Greg writes about it in his diary and Rodrick finds it the next morning and Greg chases him around through the hallways, on an elevator, and into the lobby as Rodrick attempts to give it to Holly. Greg steals it and runs through the courtyard, discovering that he was wearing nothing but underwear. He runs past a pool and accidentally runs into the women's locker room. The women discover him and chase him out. Rodrick recorded a tape of the whole thing on Grampa's TV and Greg narrates that Rodrick basically owns him and his life is over. At the talent show a few nights later, Rowley's magic performance is unable to take place, as his eight-year-old assistant Scotty (Jakob Davies) gets stage fright. Greg's mom suggests to Greg to do the show with Rowley, but Greg refuses, saying that it would be embarrassing in front of Holly. When Rodrick goes to his band, Greg follows and watches Rodrick's band member, Bill Walter (Fran Kranz), kick him out of the band he created. However, Greg is later able to both befriend Rodrick and Rowley once more when Greg offers to do the magic act with Rowley if his mom lets Rodrick perform. Rodrick performs his band act but the audience is unimpressed until they see Mom dancing on the stage and everyone gets up and starts dancing. Rodrick kicks Bill out of the band and in return for having Greg let him take part, he gives the tape of Greg running around in his underpants to him. In the end, everyone is happy with Ryan, Winnie the Pooh, Ash Ketchum, Littlefoot, Spongebob, Skipper, The Fantasy Adventure Team, Bobby, Cindy, Greg, Marcia, Peter, Jan, Oliver, Millicent, DJ, Stephanie, Michelle, Alex, Nicky, Malcolm, Mallory, Reese, Renee, Dewey, Daisy, Emily Yeung, Daniel Cook, the Jungle Adventure Crew, the Madagascar Crew, the cubs, Aladar, Taran, Jesse, Mikey, Bloom, and the rest of the characters once more. In a post-credits scene, Greg and Rowley upload the video of Mom Ryan, Winnie the Pooh, Ash Ketchum, Littlefoot, Spongebob, Skipper, The Fantasy Adventure Team, Bobby, Cindy, Greg, Marcia, Peter, Jan, Oliver, Millicent, DJ, Stephanie, Michelle, Alex, Nicky, Malcolm, Mallory, Reese, Renee, Dewey, Daisy, Emily Yeung, Daniel Cook, the Jungle Adventure Crew, the Madagascar Crew, the cubs, Aladar, Taran, Jesse, Mikey, Bloom, and the rest of the characters dancing to YouTube and they instantly become an internet sensation. In the background, they can hear Rodrick shout "Greg, you are so dead!"
- Bobby, Cindy, Oliver, Greg, Marcia, Peter, Jan, DJ, Stephanie, Michelle, Malcolm, Mallory, Resse, Renee, Dewey, Daisy, Alvin, Simon, Theodore, Brittany, Jeanette, Elanor, Sarah Baker, Jake Baker, Henry Baker, Kim Baker, Jessica Baker, Mark Baker, Mike Baker, Lorraine Baker, Nigel Baker, Kyle Baker, Spanky, Stymie, Froggy, Porky, Buckwheat, Uh-Huh, Waldo, Mary-Ann, Jane, Darla, Alfalfa, Aldo, Ethan, Marissa, Bina, Ely, Otter, Lau, Mick, Naoko, Becky O'Shea & The Little Giants Gang, Tommy, Dil, Chuckie, Phil, Lil, Kimi, Angelica, Susie, Harold, Nicole, Z, Patty, Katie, Robby, Brian, Pepper, Molly, Duffy, Kate, July, Tessie, Vada, Thomas J., Dennis The Menace & Friends, Shake It Up: Camp It Up (Flynn and his friends), Casper, Wendy, Jazmine Payne, Carly Shay, Spencer Shay, Freddie Benson, Sam Puckett, Gibby, Nigel Baker, Kyle Baker, Mike Baker, Mark Baker, Jessica Baker, Kim Baker, Sarah Baker, Jake Baker, Henry Baker, Lorraine Baker, Cooper, Dylan Schenk, Ben Hilton, Jamie, Max, Becca, Nicky, Jeannie, The Flash/Tony, Crispin, Dylan, Duncan, Sean, Tony's Brother, Juel, Erin, Shirley Temple, The Barney & Friends and the Gang, German Speaking Boy, The Chipmunks (Alvin, Simon, and Theodore), The Chipettes (Brittany, Jeanette, and Eleanor), Aldo, Ethan, Miarissa, Bina, Ely, Otter, Tilly, Tom, Tiny, Ramona, Tina, Teddy, Denise, Derek, Harry, Rusty, Walter, Max, Sharkboy, Lavagirl, Linus, Marissa, Ely, Otter, Bindi, Rosie, Kelly, Lynn, Annie, Molly, Pepper, Duffy, Kate, July, The Fraggle Rock Gang, Andy, Ruby, Gracie, Kyle, Chyna Parks, Olive Doyle, Fletcher Quimby, Lexi Reed, Cameron Parks, Nat Wolff, Alex Wolff, Thomas Batuella, Allie DiMeco, David Levi, Qaasim, Cooper Pillot, Jesse Draper, Michael Jackson & Friends, Michael Jackson Badder, Spanky, Stymie, Froggy, Porky, Buckwheat, Uh-Huh, Waldo, Mary-Ann, Jane, Rascals #1, 2, 3, and 4, Friends of Stymie and Uh-huh, Darla, Alfalfa, Little Carbon Soldiers, Becky O'Shea, Junior Floyd, Jake Berman, Rudy Zolteck, Tad Simpson, Hanon, Marcus, Timmy Moore, Nubie, Johnny Vennaro, Briggs, Patterson, Priscilla O'Shea, Murphy, Keith, Marcus, Hector, Jessica, Lisa, Shock, Pete and Pete, Pablo, Tyrone, Tasha, Uniqua, Austin, Paul, The Oslen Twins, Calvin Cambridge, Murph, Ox, Marlon, Reg Stevens, Max Keeble, Megan, Robe, Kevin McCallister, Alex, Leah, Matilda, Penelope, Matthew, Dwayne, Steve, Robert, Nelly K., Sonny, Tawni Hart, Chad Dylan Cooper, Nico Harris, Grady Mitchell, Zora Lancaster, the Baby-Sitters Club gang, Simba, Nala, Timon, Pumbaa, Baloo, Kovu, Kiara, Uncle Max, Ma, Taran, Princess Eilonwy, Fflewddur Fflam, Gurgi, Jesse Greenwood, Elvis, Randolph Johnson, Nadine, The Goonies (Mikey Walsh, Brand Walsh, Mouth Devereaux, Data Wang, Chunk Cohen, Andy Carmichael, Stef Steinbrenner, and Sloth Fratelli), Scooby-Doo, Shaggy Rogers, Fred Jones, Daphne Blake, Velma Dinkley, Yogi Bear, Boo-Boo Bear, Snagglepuss, Huckleberry Hound, Quick Draw McGraw, Augie Doggie and Doggie Daddy, Wally Gator, Magilla Gorilla, Top Cat, Peter Potamus, Woody Woodpecker, Ttark, Toaster, Lampy, Radio, Blanky, Kirby, Fievel Mousekewitz, Tiger, Tony Toponi, Tanya Mousekewitz, Yasha Mousekewitz, Papa Mousekewitz, Mama Mousekewitz, Charlie Barkin, Itchy Itchiford, Hubie, Rocko, Jack Skellington, King Louie, Genie, Louis, Sebastian, Alex, Marty, Melman, Gloria, King Julien, Maurice, Mort, Roger Rabbit, and The Entire LionKingHeart Fantasy Films team and the rest of the characters will guest star in this film.