Malaria was once home of fertile farm lands, but is now a dreary place to live ever since permanent clouds enveloped the place. As a result, King Malbert (voice of JAY LENO) concocted a scheme to raise capital by extorting the rest of the world with the threat of unleashing something truly horrible unless everyone pay up to keep it leashed.
Every year, the land's evil scientists strive to create such monsters and such, with the annual competition just a week away. Igor (voice of JOHN CUSACK) has long dreamed of being such an evil scientist, but the hunch on his back meant he was automatically assigned to go to Igor school to learn how to become an assistant to real evil scientists.
The only problem is that he's so much better of an inventor than his master, Dr. Glickenstein (voice of JOHN CLEESE), whose every attempt has failed. That's unlike Igor's creations that might not be perfect but have survived, including the suicidal, buck-toothed rabbit Scamper (voice of STEVE BUSCEMI) who's afflicted with immortality, and Brain (voice of SEAN HAYES), a nervous bit of gray matter transported around inside a jar atop a dolly.
King Malbert hates that the reigning evil scientist champion, Dr. Schadenfreude (voice of EDDIE IZZARD), is becoming more popular than him, and thus hopes that Dr. Glickenstein can concoct something to best him. Unfortunately for him, the evil scientist has recently perished in one of his experiments, but Igor sees that as his chance to create something under the guise of his late master.
Accordingly, and with the help of Scamper and Brain, he creates a towering Frankenstein type monster, assembled from a hodgepodge of parts, including an evil bone that will make it the most feared being in the land. But Igor is shocked when the bone doesn't work and his creation is subjected to acting theory, thus turning his monster into the sweet-natured Eva (voice of MOLLY SHANNON) who dreams of being a starlet
From that point on, Igor scrambles to activate her evil bone to turn her bad, all while Dr. Schadenfreude and his shape-shifting assistant, Jaclyn (voice of JENNIFER COOLIDGE), sometimes also seen as Heidi (voice of JENNIFER COOLIDGE), try to get their hands on Eva in order to overthrow King Malbert and take over Malaria.