Yarborough was born in Chandler in Henderson County west of Tyler, the seventh of Charles Richard Yarborough and the former Nannie Jane Spear's nine children. He was appointed to West Point in 1919 but dropped out to become a teacher. Yarborough attended Sam Houston State Teachers College and worked his way into the University of Texas at Austin. He graduated from the University of Texas Law School in 1927 and practiced law in El Paso until he was hired as an assistant attorney general in 1931 by the state Attorney General James V. Allred.

Yarborough was an expert in Texas land law and specialized in prosecuting major oil companies that violated production limits or failed to pay oil royalties to the Permanent School Fund for drilling on public lands. He earned renown for winning a million dollar judgment against the Mid-Kansas Oil and Gas Company for oil royalties, the second largest judgment ever in Texas at the time. After Allred was elected governor, he appointed Yarborough to the bench in 1936, making him the 53rd District judge for Austin's Travis County. Yarborough was confirmed in that office by an election later the same year. Yarborough's first run for state office resulted in a third place finish in the Democratic primary for state attorney general in 1938 against the sitting lieutenant governor. He served in the U.S. Army during World War II after 1943 and achieved the rank of lieutenant colonel.

Yarborough was urged to run again for state attorney general in 1952, and he planned to do so until he received a personal affront from Governor Allan Shivers who told him not to run. Texas Secretary of State John Ben Shepperd resigned in the spring of 1952 and was elected attorney general that year. He served two two year terms. Angered at Shivers, Yarborough ran in the gubernatorial primaries in 1952 and 1954 against the conservative Shivers, drawing support from labor unions and liberals. Yarborough denounced the corrupt "Shivercrats" for veterans' fraud in the General Land Office and for endorsing in 1952 and 1956 the Republican Eisenhower / Nixon ticket, instead of the Democrat Adlai Stevenson of Illinois. Shivers portrayed Yarborough as an integrationist supported by communists and labor unions. The 1954 election was particularly nasty in its race - baiting by Shivers as it was the year that Brown v. Board of Education was decided, and Shivers made the most of the court decision in order to play on voters' fears. Yarborough, however, nearly upset Shivers.

In 1956, Yarborough made it to the primary runoff for governor against U.S. Senator Price Daniel. Texas historian J. Evetts Haley ran in the primary to the political right of both Daniel and Yarborough but polled few votes. After being endorsed by former opponent and former Governor W. Lee O'Daniel, and making aggressive attacks on the Shivers backed candidate, Yarborough looked to win the runoff, but instead he trailed Daniel by about nine thousand votes. It is believed (by Yarborough, his supporters, and biographer) that the election was stolen because of irregular voting in East Texas and that Yarborough really won the runoff by thirty thousand. Nevertheless, Yarborough's runs for governor had raised his stature and popularity in the state as he had been campaigning for six straight years for office.

When Daniel resigned from the Senate in 1957 to become governor, Yarborough ran in the special election to fill the empty seat. With no runoff then required, he needed only a plurality of votes to win. Ironically, his many runs for governor made him the best positioned candidate. Yarborough won the special election with 38 percent of the vote to join fellow Texan Lyndon B. Johnson in the Senate.

In office, Ralph Yarborough was a very different kind of Southern senator. He refused to sign the Southern Manifesto opposing integration and supported national Democratic goals of more funding for health care, education, and the environment. Himself a veteran, he worked to expand the G.I. Bill to Cold War veterans.

In 1958, Ralph Yarborough easily defeated conservative William A. Blakley of Dallas, who was backed by Yarborough's long time party rival, Governor Daniel, in the Democratic primary and then cruised to victory in the general election against Republican Roy Whittenburg of Amarillo. In 1962, Whittenburg ran unsuccessfully for governor in the Republican primary against Jack Cox of Houston, who would in turn lose to Yarborough's intraparty rival, John Connally. During his first full term, Yarborough worked for a bill signed by President John F. Kennedy to designate Padre Island as a national seashore.

Ralph Yarborough rode in the Dallas motorcade where John F. Kennedy was assassinated on November 22, 1963. Yarborough was in the same convertible as Vice President Lyndon B. Johnson, Lady Bird Johnson, and United States Secret Service agent Rufus Youngblood, who protected all three of them with his body when shots were fired at Kennedy only two cars away from the presidential limousine. A sobbing Yarborough announced Kennedy's death at Parkland Memorial Hospital by saying: "Excalibur has sunk beneath the waves."

In 1964, Yarborough again won the primary without a runoff and went on to general election victory with 56.2 percent in LBJ's 1964 Democratic landslide. His Republican Party (GOP) opponent was future president George H. W. Bush who attacked Yarborough as a left wing demagogue and for his vote in favor of the Civil Rights Act of 1964. Yarborough denounced Bush as an extremist to the right of that year's GOP nominee for president Barry M. Goldwater and as a rich easterner and a carpetbagger trying to buy a Senate seat. It has since been learned that then Governor Connally was covertly aiding Bush instead of party nominee Yarborough against President Johnson's wishes by teaching the techniques of split ticket voting. In that same election, Connally easily defeated Bush's ticketmate, Jack Crichton, a Dallas oil and natural gas industrialist.

Although Yarborough supported Johnson's domestic agenda, he went public with his criticism of Johnson's foreign policy and the Vietnam War after Johnson announced his retirement. Yarborough supported Robert F. Kennedy until his assassination, then supported Eugene McCarthy until his loss in Chicago, and finally backed Hubert Humphrey for President in the pivotal campaign of 1968. In 1969, Senator Yarborough became chairman of the Senate Committee on Labor and Public Welfare.

In 1970, South Texan businessman and former Congressman Lloyd Bentsen, won a 54% to 46% upset victory against Yarborough in the Democratic primary, when Yarborough was focusing on the general election again against Bush. Bentsen played on voters' fears of societal breakdown and urban riots and made an issue of Yarborough's opposition to the Vietnam War. Bentsen said that Yarborough was a political antique. Said Bentsen, "It would be nice if Ralph Yarborough would vote for his state every once in a while." Bentsen went on to win the general election against George H.W. Bush.

In 1972, Ralph Yarborough made a comeback effort to win the Democratic nomination for U.S. Senator as a challenger of Republican Senator John Tower, who as a young man had once circulated Ralph Yarborough stickers. Yarborough won the first round of the primary and came within 526 votes of winning the primary runoff. Yarborough again made accusations of vote fraud from the conservative wing. He lost in the primary runoff to a former U.S. Attorney, Barefoot Sanders, in an anti - incumbent sweep after the Sharpstown Bank stock Scandal despite neither being an incumbent nor involved at all with the scandal.

Ralph Yarborough never again sought public office.

Yarborough died in 1996 in Austin. He is interred at the Texas State Cemetery beside his wife, the former Opal Warren (1903 - 2002), a native of Murchison in Henderson County, Texas. The Texas State Cemeterty is sometimes called "the Arlington of Texas." Also buried there are Yarborough's old intraparty rivals, Allan Shivers and John Connally. Yarborough left a legacy in the modernization of the state of Texas and achieved political power when Texas had a native son, Lyndon Johnson, in the White House. He was combative with the dominant industries of oil and natural gas and pushed for the petroleum industry to pay a greater share of taxes.

Yarborough also was one of the last of the New Deal Democrats and powerful liberals in Texas state politics. (He was followed by the moderately liberal Bentsen and the conservative Phil Gramm). Yarborough is remembered as the acknowledged "patron saint of Texas liberals." Supporters and former aides that have since risen to prominence include Jim Hightower, Ann Richards, and Garry Mauro.

The University of Texas at Austin Press published a biography titled, Ralph W. Yarborough: The People's Senator, by Patrick L. Cox. It features a foreword written by Sen. Edward Kennedy (D-MA).

The Yarborough Branch of the Austin Public Library was named in Ralph Yarborough's honor.