He ousted the appointed U.S. Senate incumbent, J. Howard Edmondson, and won a 1964 special election to finish Robert S. Kerr's term, narrowly defeating football coach Bud Wilkinson.

Harris strongly supported the Great Society programs and criticized President Lyndon B. Johnson's handling of the Vietnam War.

[2] Harris attended the University of Oklahoma (OU) on a scholarship, graduating in 1952 with a bachelor's degree in history and political science.

[3] In 1964, Harris ran to serve the remainder of the Senate term of Robert S. Kerr, who had died in office.

[1][2] The general election was a high-profile campaign against the Republican nominee, legendary Oklahoma Sooners football coach Bud Wilkinson.

[1] Despite being quite liberal in an increasingly conservative state, Harris was elected to a full term in 1966, defeating attorney Pat J. Patterson, by 47,572 votes.

Dirksen's amendment had enthusiastic political support in Oklahoma, but Harris opposed it in a public letter: "I believe in the separation of church and state and I believe prayer and Bible reading should be voluntary".

[1] Harris briefly chaired the Democratic National Committee, preceded and succeeded in that position by Larry O'Brien.

[1] In 1970, Harris was a major player in the legislation to restore to the inhabitants of the Taos Pueblo 48,000 ac (19,425 ha) of mountain land that President Theodore Roosevelt had taken and designated as the Carson National Forest early in the 20th century.

[11] The struggle was particularly emotive since this return of Taos land included Blue Lake, which the Pueblo consider sacred.

In doing so, he had to overcome powerful fellow Democratic Senators Clinton Anderson and Henry M. Jackson, who firmly opposed returning the land.

"[12] In 1971, Harris was the only senator to vote against confirming Lewis F. Powell Jr. as Associate Justice of the Supreme Court of the United States.

[14] Harris did not seek another Senate term in 1972 and instead ran for president, but failed to attract support and ended his campaign after only 48 days.

[3] After a surprising fourth-place finish in the 1976 Iowa caucuses, Harris coined the term "winnowed in", saying, "The winnowing-out process has begun and we have just been 'winnowed in'."

In a 2023 interview, he expressed support for President Joe Biden, saying concerns about Biden's age were unfounded, and strongly criticized former President Donald Trump for his attempts to overturn the 2020 presidential election and the consequent January 6 United States Capitol attack.