In the manga, Mandark confronts an infiltration team consisting of Numbuh 5, Mac, Bloo, and Dee Dee. The group demands his Pase-Pulse-O-Tron needed to complete the Electro-Pulse Cannon. Though initially defiant, his infatuation with Dee Dee led him to easily and willingly hand it over on the condition that he came along. Together with a reluctant Dexter, they program the EPC to disable the biggest of the first three Terrafusers that landed on Earth. However, Mandark's love for Dee Dee also distracted him, leading to a fatal error that prevented the cannon from launching at a crucial moment.
In the Past, Mandark can be found in front of his company building in Tech Square. He no longer uses his old lab now that his old house in Genius Grove has fallen victim to the Fusion invasion and has been turned into an Infected Zone. Though he is against Fuse's invasion, his rivalry with Dexter often leads him to undermine his nemesis' attempts to turn the tides of the war to gain glory for himself.
Mandark's love of Dee Dee also caused him to be manipulated by her evil doppelganger, Fusion Dee Dee, making him steal Dexter's wrench (which Fuse uses to make a Fusion Dexter). Through the efforts of the original Dee Dee, and her Imaginary Friend, Koosy, Fusion Dee Dee was defeated and Mandark realized his mistake.
Aside from Dexter, Mandark doesn't get along very well with Mojo Jojo or Vilgax, as he believes that both of them are trying to steal his company's secrets. Fusion Ben was able to exploit this fact in order to cause the three to come together in a battle royal in the Skypad Space Port Infected Zone. Fortunately, the battle was quelled thanks to the original Ben and the three villains returned to being bitter enemies.
During the mission to face Fusion Mandark for the Mandark Nano, Fusion Mandark took control of some of his Mandroids and sent them to attack the player in his lair. The player successfully destroys all of them, though not without upsetting Mandark, and defeats the Fusion.
When Planetoid Fusion broke off from Planet Fusion and headed for Earth, Dexter asked Mandark for a part for an Ion cannon he was building to shoot the planetoid down. What Dexter didn't know was that Mandark had sabotaged the part to render the Ion cannon useless, leaving his new weapon in the Really Twisted Forest alone to defend the Earth. Using a missile array borrowed from Vilgax, Mandark fine-tuned his weapon for its mission. Ironically, Vilgax had tampered with both Dexter's and Mandark's cannons so that they would hit Planet Fusion instead of it's planetoid. The planetoid itself was destroyed by Courage when he reversed the polarities on a UFO magnet in Nowhere that tore the planetoid from its foundation, thus crushing it and leaving Mandark humiliated.
To further exploit Fuse's weakness to Imaginary Energy, Mandark has enlisted Bloo and Mac to participate in a study that requires the best Kid/Imaginary Friend pair there is. He is currently building a research center called the Imaginasium near Foster's Home to initiate the research project. The construction is being overseen by Frankie, who constantly gets into quarrels with Mandark Industries Representatives, and even Mandark himself, about the structure's display.
Among all the characters from Dexter's Laboratory, Mandark is the only one being mocked as the designers say that he's still hasn't matured since his wardrobe hasn't updated.
- Fusion Mandark, at first, was strangely a level lower than the player (Level 18), but that was eventually fixed.
- Mandark's head is bigger in the show than in the game.
- Future Mandark misses the others.