He became a national figure in Democratic Party politics, often feuding with fellow Democrat Pat Brown, who was Governor of California from 1959–1967, and was a case-study in the James Q. Wilson treatise on machine politics, The Amateur Democrat.

As an early supporter of the Presidential campaign of Robert F. Kennedy in 1968, Unruh emerged as a pivotal figure in the run-up to the Democratic Convention. He helped Kennedy capture the California Primary in June of that year, but an assassin's bullet that night ended the campaign. In the melee that ensued, Unruh assisted in keeping suspect Sirhan Sirhan from the reach of angry Kennedy supporters. After an unsuccessful effort, led by Unruh and Mayor Richard J. Daley of Chicago, to draft Senator Edward M. Kennedy of Massachusetts, he endorsed Eugene McCarthy at the 1968 Democratic Convention in Chicago.

He left the legislature to run for Governor against Ronald Reagan in 1970, then was a candidate for Mayor of Los Angeles in 1973. He lost both elections, but was elected State Treasurer in 1974, and served from 1975 until he died in office of prostate cancer on August 4, 1987. The University of Southern California Department of Political Science includes an institute named the Jesse M. Unruh Institute of Politics.

According to one apocryphal tale, he was nicknamed "Big Daddy" by Raquel Welch, when the two were allegedly involved with one another. Raquel Welch denies this claim; it is more likely that the nickname was a reference to the character in the Tennessee Williams' play, "Cat on a Hot Tin Roof."

His religion was described as Protestant, and he was a member of the American Legion. He married twice, and had five children. He was buried in Santa Monica, California.

Famous Quotes
"Money is the mother's milk of politics."

"If you can't take their money, drink their liquor, fuck their women, and then come in here the next day and vote against them, you don't belong here."