Garner was born near Detroit, Red River County, Texas, and was a Cherokee Indian on his father's side. He studied law, was admitted to the bar in 1890, and began practice in Uvalde, Uvalde County, Texas. He was a judge of Uvalde County from 1893 to 1896 and a member of the state House of Representatives from 1898 to 1902.

Garner was elected as a Democrat to the United States House of Representatives in 1902 from a newly created congressional district covering tens of thousands of square miles of rural South Texas. He was elected from the district fourteen subsequent times, serving until 1933.

Garner's hard work and integrity made him a respected leader in the House, and he was chosen to serve as minority floor leader for the Democrats in 1929, and then as Speaker of the United States House of Representatives in 1931.

In 1932, Garner ran for the Democratic Presidential nomination, becoming one of New York Governor Franklin Roosevelt's most serious opponents for the nomination. When it became evident that Roosevelt would win the nomination, Garner cut a deal with the front-runner, becoming Roosevelt's Vice Presidential candidate. He was re-elected to the Seventy-third Congress on November 8, 1932, and on the same day was elected Vice President of the United States. He was reelected Vice President in 1936 and served in that office from March 4, 1933 to January 20, 1941.

Garner, always the character, once described the office of the vice presidency as being "not worth a bucket of warm piss" (at the time reported with the bowdlerization "spit").

During Roosevelt's second term, the previously warm relationship between Garner and Roosevelt quickly soured, as Garner disagreed sharply with Roosevelt on a wide range of important issues. Garner supported federal intervention to break up the first sit-down strike, supported a balanced federal budget, opposed packing the Supreme Court with additional judges, and opposed executive interference with the internal business of the Congress.

During 1938 and 1939, numerous Democratic party leaders urged Garner to run for President in 1940. Garner saw himself as the champion of the traditional Democratic Party establishment, which often clashed with supporters of Roosevelt's New Deal. Gallup polls showed that Garner was the favorite among Democratic voters, presuming that Roosevelt would not run for a third term.

Though he never declared his candidacy, Roosevelt quietly made it known that he would seek a third term. Even though this decision made it highly unlikely that Garner would win the nomination, he stayed in the race anyway, because he opposed much of what the President stood for, and opposed the idea of anyone having a third term as President.

Roosevelt beat Garner soundly in the Democratic primaries, and won re-nomination at the Democratic National Convention on the first ballot.

Garner stepped down as Vice President in January 1941, ending a 46-year career in public life. He retired to Uvalde for the last 26 years of his life, where he managed his extensive real estate holdings, spent time with his great-grandchildren, and fished. Throughout his retirement, he was consulted by active Democratic politicians, and was especially close to Harry S. Truman. At the time of his death he was the longest lived Vice President of the United States, a record that still stands as of 2006.