Byrns was born in Robertson County, Tennessee. A graduate of public schools, he displayed a strong early interest in politics and was elected to the Tennessee House of Representatives in 1894 and reelected in 1896 and 1898. In 1900 he was elected to the Tennessee State Senate.

In 1902 he ran for district attorney of Davidson County, Tennessee but was defeated - his only unsuccessful political race in 18 efforts. In 1908, Byrns received the Democratic nomination for U.S. Representative and was elected in November of that year to a term beginning March 4, 1909. He served in the House for the rest of his life.

Byrns was widely respected and his influence grew as his seniority did. He was chairman of the Democratic Congressional Campaign Committee from 1928 to 1930. In 1931 he was appointed chairman of the powerful House Appropriations Committee and in 1933 became House Majority Leader. In 1935 he became Speaker of the House.

Byrns was serving as Speaker at the time of his unexpected death, which occurred in Washington, D.C., and was already planning to run for reelection. In a display of respect for both the man and his office, his funeral was held within the walls of the Capitol. He was interred at Mount Olivet Cemetery in Nashville. His son Jo Byrns, Jr. later served a single term in the House.

Jo Byrns High School, near Adams, Tennessee in his native Robertson County, is named in his honor.

Preceded by: Henry T. Rainey Speaker of the U.S. House of Representatives January 3, 1935 - June 4, 1936 Succeeded by: William B. Bankhead