After living for fifteen years in Oklahoma City, Ruscha moved permanently to Los Angeles where he attended the Chouinard Art Institute from 1956 to 1960. By the mid sixties, the artist had published his first photography book, Twenty-Six Gasoline Stations, and had completed a series of paintings that displayed with great precision a single word against a flatly lit background. Ruscha was associated at this time with the Ferus Gallery Group, which also included such artists as Edward Moses, Ken Price, Robert Irwin, and Edward Kienholz.

From 1969 to 1970, he was a guest professor at the University of California. Ruscha produced his first film entitled Premium soon following his time at the university, and continued work on his textual paintings. Some works include such figurative and verbal symbols as egg yolk, blood, and gunpowder. Ruscha worked to connect linguistic symbols with visual idioms and to elevate them to the point of the cosmic.

During the eighties, Ruscha executed a series of drawings incorporating vegetable pigment and depicting mysteriously cast light and phrases such as 99% DEVIL, 1% ANGEL. The artist's use of light beams may be attributed to his Catholic upbringing; illumination as a symbol of the divine comes into play in many of his paintings. Still, Ruscha claims no particular moral or spiritual position. In 1985, Ruscha executed his first public commission, a mural for the Miami Dade Public Library that displays the phrase Words Without Thoughts Never to Heaven Go.

Since 1990, Ruscha has produced several larger works depicting empty rooms into which light projects. He has also experimented more recently with curved canvases. Edward Ruscha's work has been shown internationally for thirty years, and is permanently represented in many major museum collections.