Alben Willie Barkley was born on November 24, 1877, in a log cabin near Lowes, Kentucky. He was born Willie Alben Barkley, but went by Alben and had his names reversed when he was old enough. His father was a poor tobacco farmer and railroad worker. As a boy, Barkley had to spend a good deal of his time working and received a limited education in county schools. When he was fourteen, he was able to afford school at a small college in Clinton, Kentucky, by working as a janitor. When he graduated from Marvin College in 1897, he enrolled at Emory College in Georgia for a year but had to leave because of limited funds. By 1902, he had saved up enough money to attend a summer law course at the University of Virginia. While in Charlottesville, Virginia, he studied Thomas Jefferson and took from him an enduring ideal of the common man that informed his political beliefs throughout his career.

Barkley began his career as a prosecuting attorney in McCracken County, Kentucky, and then as a county judge. He served as a judge until 1912, when he was elected to the U.S. House of Representative as a member of the Democratic Party. Barkley spent almost fifteen years there before being elected to the Senate in 1926. While in the House, he was a loyal supporter of President Woodrow Wilson's agenda and established a strong liberal voting record. After his election to the Senate, he rapidly rose to positions of leadership, becoming assistant majority leader by 1932. When Majority Leader Joseph Robinson died in 1937, Barkley entered into a contentious battle to succeed him. With strong support from President Franklin Roosevelt, Barkley won the contest by a single vote. During the Roosevelt years, Barkley was one of the most powerful men in his party and an indispensable ally in ushering critical components of the New Deal through Congress. By the time he took over as majority leader, however, Roosevelt's ambitious agenda had opened stark divisions in the Democratic Party between progressive and conservative factions. Despite a 76-16 Democratic majority, Barkley often had trouble forging workable coalitions.

Barkley may have contended for the vice presidential nomination in 1944 and eventually ascended to the presidency had it not been for a dramatic confrontation with President Roosevelt earlier that year. After Roosevelt offered stinging remarks and a veto in response to a tax bill he deemed insufficient, Barkley delivered a dramatic speech in which he rebuked the administration, rallied the Senate to override the bill, and resigned his post as majority leader. He was unanimously reelected the next day but the split with Roosevelt took him out of vice presidential contention.

In the 1948 presidential election, President Harry Truman wanted to select Supreme Court Justice William O. Douglas as his running mate, but Douglas refused the offer. Truman then offered the job to Barkley, and he accepted. Both Truman and Barkley campaigned vigorously and pulled off one of the most stunning upsets in the history of American politics. At age seventy-one, Barkley was the oldest man ever to take the office of vice president. A year later, he also became the only incumbent vice president to marry when he wed Jane Hadley.

Barkley admired the way President Franklin Roosevelt's first vice president, John Nance Garner, had used his office and personal attributes to make the most of an office with few formal responsibilities. He believed a vice president "can exercise considerable power in the shaping of the program of legislation which every administration seeks to enact," as long as they had the respect of the President and the Congress. While in office, Barkley was a valued member of the administration and respected presiding officer of the Senate. He was also the first vice president to sit on the newly-created National Security Council.

When Truman declined to seek another term, Barkley sought the 1952 presidential nomination but attracted little support, mainly due to his age. He briefly retired from public life before being reelected to the Senate again in 1954. On April 30, 1956, Barkley traveled to Washington & Lee University in Lexington, Virginia, for a speaking engagement. At the end of his speech, he discussed the novelty of once again sitting with the freshmen Senators. "I am glad to sit in the back row," said Barkley, "For I would rather be a servant in the house of the Lord than to sit in the seats of the mighty." With these dramatic words, Barkley concluded his speech and collapsed dead of a heart attack.