Born in Bakersfield, California, he attended public school and graduated from Chico State College in 1930 and from the University of California Hastings College of Law in 1933.

He was admitted to the bar in 1933 and commenced practice in Corning, California, and served as district attorney of Tehama County, California from 1934 until 1942, when he was elected to the California Senate, serving in that body in 1943.

He was elected on August 31, 1943, as a Democrat to the 78th Congress to fill the vacancy caused by the death of Harry L. Englebright and was reelected to the following six Congresses, serving, in toto, from 1943 until 1959. While in the United States House of Representatives he was chairman of the U.S. House Committee on War Claims for the 79th Congress and chairman of the U.S. House Committee on Interior and Insular Affairs for the 84th and 85th Congresses.

He was elected as a Democrat to the United States Senate in 1958 and began serving in 1959.

On June 10, 1964, during the roll call for the historic, successful effort to break the filibuster on what would become the Civil Rights Act of 1964, when the clerk reached "Mr. Engle," there was no reply. A brain tumor had robbed Senator Engle of his ability to speak. Slowly lifting a crippled arm, he pointed to his eye, thereby signaling his affirmative vote ("aye"). Few who witnessed Engle's brave act forgot it. Nine days later the Senate approved the act itself - producing one of America's towering 20th century legislative achievements.

Engle died in Washington, D.C. a month and a half later, aged 52.

Trinity Lake, in California's Trinity County, was renamed for Clair Engle, although the name Trinity Lake continued to be commonly used, and eventually the lake's name reverted back.