Wiley was raised in Indiana, Texas, and Richland, Washington. In high school, his highly influential art teacher, James McGrath, recognized Wiley's talent and encourage him to pursue an art career. Wiley received a full-ride scholarship to the California School of Fine Arts (later to become the San Francisco Art Institute), along with fellow high school friends Robert Hudson and William Allan, who also received scholarships to the school. There he earned his BFA in 1960 and his MFA two years later.
In 1963, Wiley joined the faculty of the UC Davis art department with Bay Area Funk Movement artists Robert Arneson, Roy DeForest, and Pop artist Wayne Thiebaud. During that time Wiley instructed students, including Bruce Nauman, Deborah Butterfield, Richard Shaw, Stephen Kaltenbach and Stephen Laub. According to Dan Graham, the literary, punning element of Nauman's work came from Wiley. Wiley also acknowledges the effect Nauman had on his own work.
His first solo exhibition was held at the San Francisco Museum of Modern Art in 1960. In the late 1960s Wiley collaborated with the minimalist composer Steve Reich and created the album artwork for Reich's first major record label release, "Violin Phase".
Over the course of his career, Wiley has pursued artistic expression in almost every conceivable medium, from watercolors, paintings, collage, found object constructions, sculpture and printmaking, to music, performance art, theater and film. He collaborated on several films with filmmaker Robert Nelson, including "The Off-Handed Jape", and the avant-garde epic, "The Great Blondino". He has collaborated with the San Francisco Mime Troupe and R.G. Davis in both theater and film. He has created art projects with Robert Hudson, William Allan, Richard Shaw and Terry Allen. He produced a series of popular avant-garde theatrical shows at UC Davis titled, "Out Our Way". Wiley continued to build upon his growing stature as a major artist with works appearing in the Venice Biennial (1980) and Whitney Biennial (1983). He also had major exhibitions at the San Francisco Museum of Modern Art (1981), M. H. de Young Memorial Museum, San Francisco (1996), and the Corcoran Gallery of Art, Washington, D.C. (2005).
In 2009, the Smithsonian American Art Museum presented a retrospective of Wiley's career titled, What's It All Mean: William T. Wiley in Retrospect, from October 2, 2009 through January 24, 2010. A review in the Wall Street Journal stated: "Mr. Wiley's work is unlike any other in recent art... He is less a contemporary artist than a national treasure." In 2010, the retrospective moved to the Berkeley Art Museum, from March 17 to July 18. The catalogue for the retrospective, "What's It All Mean: William T. Wiley in Retrospect", was co-published by the Smithsonian American Art Museum and University of California Press.
Recently Wiley has exhibited with the Parker Gallery in Los Angeles, and in 2019 had his third solo show with the Hosfelt Gallery, in San Francisco: "Sculpture, Eyes Wear Tug Odd." In 2020, Parker Gallery presented a survey of Wiley's artwork from the 1960s to present day in NYC, "Real Eye On Change". Also in 2020, Wiley was featured in the "Pop, Minimal and Figurative Art" show at SFMOMA, with an exhibit titled "Con-Fusion-Ism" curated by Zully Adler. IN 2021, Wiley's first posthumous gallery show, "Monumental", was exhibited at the Hosfelt Gallery. In 2022, "William T. Wiley and the Slant Step: All On The Line" debuted at the UC Davis Manetti Shrem Museum, curated by Dan Nadel.
Among the many public collections holding works by William T. Wiley are the Whitney Museum of American Art, the Museum of Modern Art (New York), the San Francisco Museum of Modern Art, the Los Angeles County Museum of Art, the Art Institute of Chicago, the Smithsonian American Art Museum (Washington, D.C.), the Museum of Fine Arts, Boston, the Van Abbemuseum (Eindhoven, Netherlands), the Walker Art Center (Minneapolis), the San Jos Musuem of Art, the Baltimore Museum of Art, the Di Rosa Center for Contemporary Art (Napa, California), the Dallas Museum of Art, the Denver Art Museum, the Honolulu Museum of Art, the Minneapolis Institute of Arts,, the New Britain Museum of American Art (New Britain, Connecticut), the Nelson-Atkins Museum (Kansas City, Missouri), and the Philadelphia Museum of Art . He was the recipient of the Guggenheim Fellowship Award in 2004.