Kang and Kodos have invaded Springfield and Bart and Lisa decide to go to Professor Frink. They head to Frink's house, but he's not in so they break inside, where they discover his Rift Portal machine. Lisa and Bart enter and are transported through a rift tunnel. They eventually end up in a huge place, full of goo, hearts, cards and old video game characters. Professor Frink appears and explains to them it's a video game factory. Bart and Lisa tell Frink that Springfield is being invaded by aliens, and he suggests cheating by using "The Simpsons Game Strategy Guide", despite Lisa disliking cheating. Just when Frink is about to give them the guide, he is kidnapped by Donkey Kong, a giant video game ape. Some pages fall, and they explain the new powers.
Bart earns the Bartman's grapple. He grapples to the other side of a platform and pulls a lever so Lisa can reach him. They get inside a Mario warp pipe which transports them to another section of the factory. They follow the ape through a conveyor belt with chips and defeat some karate masters and football players who come from the "employees only" doors. With Buddha's Hand, Lisa positions some cogs to make a platform move up and down so they can get to another warp pipe. Now they are in the same place they started, but higher. After that, they get to the blood room, full of blood pools and barrels, the place where Lisa earns the super-saxophone: when played, the stunned enemies fight each other.
When Bart and Lisa find another warp pipe after deactivating the knives and "pows" generators, they get to the same starting place but at the highest point, which has a warp pipe with goo falling on it. Bart uses his slingshot to make Sonic fling off a treadmill, so the goo stops and Bart and Lisa can go ahead. Now they are in the marketing room, and have to make their way across the goo river, the karate and football men and the big moving platforms. Lisa uses Buddha's Hand to move the platforms so Bart can grapple to a warp pipe and activate it. They are transported to the ape room. Here Lisa earns the Buddha's Hand power flick: she can kick the enemies with her hand from above and send them to fly. She kicks a football player to a button, which makes a warp pipe appear and transport them across the goo river to the ape platform.
Frink is on a higher platform with ladders and Donkey Kong is throwing barrels (like Princess Peach kidnapped by Bowser in the Mario games). Now the karate and football men spawn infinitely and keep throwing fire balls and footballs to Bart and Lisa plus Donkey Kong's barrels. Lisa uses the power flick to send the ape down the goo.
Frink is now free and transports Bart and Lisa back home, but Frinks stays there with his new girlfriend, Koopa Troopa, a relationship that makes Bart and Lisa cringe at the thought.
Springfield is still being attacked by Lard Lad, the dolphins and the aliens, and the Simpson family can defeat them with their renewed powers.