At Wellman College, thousands of hamsters overrun the campus after being accidentally released by Sherman Klump, an obese but very kind-hearted professor. Meanwhile, Sherman has created an experimental formula that reconstructs the DNA of an obese person in a way that allows them to lose weight more easily.
After his lecture, Sherman meets and instantly falls in love with Carla Purty, a chemistry graduate who is a big fan of his work. After dinner with his impolite family, Sherman asks Carla out on a date, which she accepts, much to Sherman's surprise. The date begins well with Carla showing admiration for Sherman's work, but the club's obnoxious guest comedian, Reggie Warrington, publicly mocks him about his weight. Sherman becomes depressed and, after having a nightmare in which he becomes a rampaging hungry giant that destroys the city, he tests his serum on himself, losing 250 pounds within seconds. Overwhelmed by his immediate weight loss, he goes out and buys copious amounts of normal-sized clothing to celebrate, and a $47,000 Dodge Viper RT/10 sports car on his faculty expense account. However, Sherman discovers that the effects of the serum are only temporary.