[2] When World War II focused President Franklin D. Roosevelt's attention on foreign affairs, Barkley gained influence over the administration's domestic agenda.

Truman selected him as his running mate for the upcoming election, and the Democratic ticket scored an upset victory against Thomas Dewey and Earl Warren of the Republican Party.

When Truman announced that he would not seek re-election in 1952, Barkley began organizing a presidential campaign, but labor leaders refused to endorse his candidacy because of his age, and he withdrew from the race.

[13] In the difficult economy of late 1891, relatives convinced Barkley's father to sell his farm and move to Clinton, to pursue opportunities as a tenant wheat farmer.

"[45] Charging that Barkley's membership in Woodmen of the World was politically motivated, Hendrick ended up attacking the organization itself, angering the approximately 5,000 club members in the First District.

[53] He sponsored an amendment to the Lever Food and Fuel Act forbidding the use of grain – rendered scarce by World War I and a poor harvest in 1916 – to make alcoholic beverages.

[57] Attempting to unite the party and prevent a Republican victory, Black invited Barkley, who had not been linked to either leader despite his support for prohibition, to be temporary chairman of the 1919 state Democratic convention.

[60] Barkley supported U.S. neutrality in World War I and endorsed Wilson's plan to purchase merchant ships for the U.S. instead of paying foreign carriers to travel waters containing German U-boats.

[61] His position was popular in his district, as 80% of the dark tobacco grown in western Kentucky was sold overseas, and higher shipping costs adversely affected profits.

[65] Republican Warren G. Harding defeated Cox in the general election, and Barkley found common ground with him on issues such as the creation of the Veterans' Bureau and the passage of the progressive Sheppard–Towner Act.

[68] According to Barkley biographer James K. Libbey, the establishment of such an organization, and not necessarily a desire to become governor, may have motivated him to announce his candidacy for the Democratic gubernatorial nomination on November 11, 1922.

[68][70] Beckham, leader of the liberal wing, intended to run, and his surrogates, particularly Louisville Courier-Journal editor Robert Worth Bingham, began a "Business Man for Governor" campaign in late 1922.

[13] His proposals for a statewide highway system and improvements in education were popular, but coal mining and horse racing interests, based mostly in eastern Kentucky, opposed him.

[84][86] Barkley contrasted his impoverished upbringing with Ernst's affluent lifestyle as a corporate lawyer, and also attacked him for supporting Michigan senator Truman Handy Newberry, who resigned due to allegations of election fraud.

[87] In early 1928, Vice President Charles G. Dawes assigned him to a special committee to investigate the campaign expenditures of the leading candidates in the upcoming presidential election.

[87] Democrats considered nominating him for vice president that year, calculating that his party loyalty and appeal to rural, agricultural and prohibitionist constituents could balance a ticket headed by likely presidential nominee Al Smith, an urban anti-prohibitionist.

[100] Applause frequently punctuated the speech, with the longest interruption – a 45-minute near-riot – erupting after Barkley called for a platform plank directing Congress to repeal prohibition.

[102] In the general election, he defeated Republican Congressman Maurice H. Thatcher by a vote of 575,077 to 393,865, marking the first time in the 20th century that a Kentucky senator won a second consecutive term.

[121] After the congressional session, Barkley resumed his "Iron Man" campaign style, making between 8 and 15 speeches each day and traveling, on average, 4,500 miles (7,200 km) per week.

[132] He helped secure the Hatch Act, and The Washington Daily News called a 1940 amendment that prohibited campaigning by federally funded state employees a "monument to Alben Barkley's persistence and parliamentary skill".

[136] In November 1943, he helped draft the Connally–Fulbright Resolution for the creation of an international peace-keeping body at the end of the war, an idea he had favored since Woodrow Wilson's support of the League of Nations.

The legislators included Barkley, Ed Izac, John M. Vorys, Dewey Short, C. Wayland Brooks, and Kenneth S. Wherry, along with General Omar Bradley and journalists Joseph Pulitzer, Norman Chandler, William I. Nichols, and Julius Ochs Adler.

[148] The committee's report, delivered on July 20, 1946, exonerated Roosevelt of any blame for the attack and highlighted weaknesses in communications between branches of the U.S. armed forces, leading to the creation of the United States Department of Defense.

[111] Despite these suspicions and his contention that a ticket consisting of a Missourian and a Kentuckian lacked regional geographic balance, convention delegates persuaded Truman to take Barkley as his running mate.

[160] Truman commissioned the United States Army Institute of Heraldry to create a seal and flag for the vice president, advocated raising his salary, and increased his expense budget.

[162] In March 1949, Democratic floor leader Scott W. Lucas introduced an amendment to Senate Rule XXII to make cloture easier to achieve, hoping to end a ten-day filibuster against a civil rights bill.

[44] Barkley's most notable tie-breaking vote as vice president was cast on October 4, 1949, to save the Young–Russell Amendment that set a 90% parity on the price of cotton, wheat, corn, rice, and peanuts.

[172] Truman surprised Barkley, appearing on the Senate floor to present the medallion and a gavel made of timbers used to renovate the White House after the burning of Washington in 1814.

[177] To dispel concerns about his age (74), failing eyesight, and heart problems, Barkley arrived in Chicago for the convention and briskly walked seven blocks from the bus station to his campaign headquarters.

[177][178] The attempt was rendered moot on July 20 when a group of labor leaders, including United Automobile Workers president Walter Reuther, issued a statement calling Barkley too old and requesting that Democrats nominate someone younger like Stevenson.