Clements began his career as an Animator for Hanna-Barbera. After a few months there, he was accepted into Disney's Talent Development Program, an Animator training ground and workshop. After that, he served a two-year apprenticeship with famed Animator Frank Thomas, a supervising Animator in classic Disney films such as Peter Pan (1953), Lady and the Tramp (1955), and The Aristocats (1970). Clements made his feature debut as a character Animator on The Rescuers and Pete's Dragon in 1977. In 1981, he became the supervising Animator on The Fox and the Hound. Future partner John Musker worked as a character Animator under him, and Clements later teamed up with Musker as story artists on The Black Cauldron before they were removed from the project. In 1982, Clements proposed adapting children's book series Basil of Baker Street by Eve Titus into an animated feature and, along with story Artist Pete Young, it was pitched to Ron Miller. Because the animators were displeased with the direction of The Black Cauldron was heading, Basil of Baker Street was approved as an alternative project. Burny Mattinson and Musker were assigned as the original Directors while Dave Michener was brought in as an additional Director. Due to a shortened production schedule and multiple story rewrites, Roy E. Disney assigned Mattinson to serve as director/producer while Clements was brought in as another Director.

While working on The Great Mouse Detective, newly appointed Disney CEO and chairman Michael Eisner and Jeffrey Katzenberg issued invitations to the animation staff for their first held "gong show" session. Demanding only five new ideas, Clements went to a bookstore and discovered Hans Christian Andersen's The Little Mermaid. Clements wrote and presented a two-page treatment of Mermaid to Disney CEO Jeffrey Katzenberg at a "gong show" idea suggestion meeting, as well as conceptualized the idea of Treasure Planet. At the gong show session, Mermaid was rejected for its similarities to Splash while Planet was rejected by Eisner because Paramount Pictures was developing a Star Trek sequel with a Treasure Island angle (that went eventually unproduced). The next morning, Katzenberg approached Clements and asked him to expand his initial treatment. With Mermaid in production in 1986, Clements and Musker were later joined by Off-Broadway musical composers Howard Ashman and Alan Menken who collaborated on the song and musical score. Released in November 1989, The Little Mermaid was praised as a milestone in rebirth of Disney animation by film critics and collected a domestic gross of $84 million, cumulatively receiving $184.2 million worldwide. When work on Mermaid was wrapped, Clements and Musker re-developed their idea for Treasure Planet, but the studio still expressed disinterest. Instead, the two Directors were offered three projects in development: Swan Lake, King of the Jungle, and Aladdin. The Directors chose Aladdin because they thought the story would suit a wackier, faster-paced, and more contemporary mood than that found in recent Disney animated films.

Working from Ashman and Menken's treatment and musical score, the two delivered a story reel to Katzenberg in April 1991, which was strongly disapproved of. Jettisoning multiple characters and story ideas and the inclusion of Ted Elliott and Terry Rossio as co-screenwriters, the production team restructured the entire story in eight days. Released in November 1992, Aladdin received positive reviews from film critics, and became the first animated film to gross over $200 million in domestic grosses. Following work on Aladdin, Clements, along with Musker, resumed their work on Treasure Planet, which was again turned down by Katzenberg in 1993 who disapproved the adaptation of a classic adventure tale and setting it in outer space. A deal was struck with the two Directors to create another commercial film before he would approve Treasure Planet. Rejecting projects in development such as Don Quixote, The Odyssey, and Around the World in Eighty Days, they were later informed of Animator Joe Haidar's pitch for a Hercules feature, and signed onto the project. During production on Hercules, in 1995, Clements and Musker signed a seven-year contract deal with the studio which stipulated following Hercules, the studio would produce Treasure Planet or another project of their choosing.

With Treasure Planet completed in 2002, Clements and Musker later inherited Fraidy Cat, which was originally a project developed by Dutch animation Director Piet Kroon. However, David Stainton, then-president of Walt Disney Feature Animation, refused to green-light the project. which was followed with Clements and Musker's resignation from Disney in September 2005. When John Lasseter was appointed chief creative officer over Disney Feature Animation in February 2006, he invited Clements and Musker back to Disney to oversee production on The Frog Princess, and were officially confirmed as Directors in the following July. Later re-titled The Princess and the Frog, the film received positive reviews and grossed $267 million worldwide.

After directing The Princess and the Frog, Clements and Musker started working on an adaptation of Terry Pratchett's Mort, but obtaining the film rights prevented them from continuing with the project. To avoid similar problems, they pitched three new ideas, where by 2011, the two Directors started developing the film based on an original idea. In late 2012, the duo announced that they will be directing a new film in the Future, but they have their lips sealed for the title, the plot, and the animation style. In July 2013, it was revealed that the film, titled Moana, would be "a Polynesian tale involving the island folk and the idols made famous the world over". On November 10, 2014, Disney confirmed Moana would be released on November 23, 2016.