Clampett showed an interest in animation and puppetry from his early teens in Los Angeles. He secured a job in 1931 at the studio of Hugh Harman and Rudolf Ising where he worked on the studio's Looney Tunes and Merrie Melodies series. In his first years at the studio, Clampett mostly worked for Friz Freleng, under whose guidance Clampett grew into an able animator. In 1935, he designed the studio's first major star, Porky Pig, who appeared in Freleng's film "I Haven't Got a Hat". Clampett moved to Tex Avery's unit that same year, and the two soon developed an insanely irreverent style of animation that would set Warner Bros. apart from its competitors.
Clampett was promoted to director in late 1937, and he soon entered his personal golden age. His cartoons grew increasingly violent, irreverent, and surreal, not beholden to even the faintest hint of real-world physics, and his characters are easily the rubberiest and wackiest of all the Warner directors'. Nonetheless, he would always maintain his childlike sense of wonder (he did, after all, introduce the infantile Tweety Bird). Until he left the studio in 1946, Clampett would create some of the studio's funniest and most outrageous cartoons, including "Porky in Wackyland" (1938), "A Tale of Two Kitties" (which introduced Tweety Bird), "Coal Black and de Sebben Dwarfs" (1943), "Russian Rhapsody" (1944), "The Great Piggy Bank Robbery" (1946), and "The Big Snooze" (1946), his final cartoon with the studio. It was largely Clampett's influence that would impel the Warners directors to shed the final vestiges of Disney and enter the territory they are famous for today.
Clampett worked for a time at Screen Gems, but in 1949, he turned his attentions to television where he created the famous puppet show Time for Beany. The show would earn Clampett three Emmys and count such celebrities as Groucho Marx and Albert Einstein as fans. In 1962, Clampett created an animated version of the show called Beany and Cecil, which ran on ABC for five years.
In his later years, Clampett toured college campuses and animation festivals as a lecturer on the history of animation. In 1976 he was the focus of a documentary entitled Bugs Bunny Superstar, the first documentary to seriously examine the history of the Warner Bros. cartoons. Clampett, whose collection of drawings, films, and memorabilia from the golden days of Termite Terrace was legendary, provided nearly all of the behind-the-scenes drawings and home-movie footage for the film.