Charlesworth began to exhibit in New York and internationally with the photo-novellas Eddie Glove (1976–79), and Special Communiqués (1981). Other staged photographic series followed, including Trouble (1982–83), Fate (1984–87), Man and Nature (1988–91), Confiscated Objects (1999–2000), and Serum (2003–08).
Surveillance (1981) was the first of many of what Charlesworth termed narrative environments, works that use video and/or audio to power a narrative within a designed space. Projectile (1982), Wrong Adventures (1984), Private House (1987), Reality Street (1994) and Airlock (2004) are a few subsequent multimedia installations. Video and film works include Communiqués for Tape (1981), Robert and Roger (1985), Dateline for Danger (1987), A Stranger's Index (1990) and The Happiness Effect (2004). Throughout much of the 1990s Charlesworth worked on his feature-length experimental film project Private Enemy - Public Eye. In 1989 a book was published entitled Private Enemy, Public Eye: The Work of Bruce Charlesworth, which was also the name of a survey exhibition of his work at the International Center of Photography. The recent interactive video installation Love Disorder was featured in the 2008 Zero1 Biennial in San Jose.
Charlesworth's work has been shown at the Centre Georges Pompidou in Paris, London's Tate Gallery, The American Film Institute, the Whitney Museum of American Art, the National Museum of American Art in Washington, and the Museum of Contemporary Art in Chicago and many other museums and galleries. His work is included in the permanent collections of the Museum of Modern Art in New York, the Baltimore Museum of Art, the Metropolitan Museum of Art, the Walker Art Center in Minneapolis, the Houston Museum of Fine Arts and the Fundação de Serraives in Oporto, Portugal, among others. Charlesworth was the first artist-in-residence at the Capp Street Project in San Francisco.
Charlesworth has also been the recipient of many grants and fellowships, from the National Endowment for the Arts, the Louis Comfort Tiffany Foundation, the Jerome, Bush and McKnight Foundations. In 2007, he was awarded a John Simon Guggenheim Memorial Foundation Fellowship for his work in interactive video installation.