Rayburn was born in Roane County, Tennessee, on January 6, 1882, 24 days before Franklin D. Roosevelt, a fact noted by the news media while Roosevelt was President and Rayburn was Speaker. He was the son of Martha Clementine (Waller) and william Marion Rayburn. In 1887 the Rayburn family moved to a cotton farm near Windom, Texas. Rayburn graduated from East Texas Normal College (now Texas A&M University–Commerce) in Commerce and became a schoolteacher.

Born in Roane County, Tennessee, Rayburn moved with his family to Windom, Texas in 1887. After a period as a schoolteacher, Rayburn won election to the Texas House of Representatives and graduated from the University of Texas School of Law. He won election to the United States House of Representatives in 1912 and continually won re-election until his death in 1961. Rayburn was a protege of John Nance Garner and a mentor to Lyndon B. Johnson.

Rayburn married once, to Metze Jones (1897–1982), sister of Texas Congressman and Rayburn friend Marvin Jones. He had corresponded with her for nine years, and at the time of the wedding Rayburn was 45 and Jones was 30. Their 1927 marriage ended after only a few months; biographers D. B. Hardeman and Donald C. Bacon guessed that Rayburn's work schedule and long bachelorhood, combined with the couple's differing views on alcohol, contributed to the rift. The court's divorce file in Bonham, Texas, has never been located, and Rayburn avoided speaking of his brief marriage. In 2014 the Associated Press reported the existence of a letter Rayburn wrote to Metze after her father died in June 1926.

He won election to the Texas House of Representatives, beginning his first term in 1907. He attended the University of Texas School of Law while a state representative, and was admitted to the State Bar of Texas in 1908. During his third two-year term in the Texas House, he was elected Speaker of the House at the age of twenty-nine. The next year, he won election to the United States House of Representatives in District 4. He entered Congress in 1913 at the beginning of Woodrow Wilson's presidency and served in office for almost 49 years (more than 24 terms), until the beginning of John F. Kennedy's presidency.

Rayburn was elected House Majority Leader in 1937 and was elevated to the position of Speaker of the House after the death of william B. Bankhead. He led the House Democrats from 1940 to 1961, and served as Speaker of the House from 1940 to 1947, 1949 to 1953, and 1955 to 1961. He also served as House Minority Leader from 1947 to 1949 and from 1953 to 1955. Rayburn preferred to work quietly in the background and allowed committee chairmen to retain much of the power in the House. He refused to sign the Southern Manifesto and was influential in the construction of U.S. Route 66. He served as Speaker until his death in 1961, and was succeeded by John william McCormack.

On September 16, 1940, at the age of 58, and while serving as Majority Leader of the United States House of Representatives, Rayburn became Speaker of the House upon the sudden death of Speaker william Bankhead. Rayburn's ascension to the speakership was surprisingly rapid; that including Bankhead, the three Speakers prior to Rayburn died in office within six years. (Henry Thomas Rainey died in 1934 and Jo Byrns in 1936.)

Rayburn was well known among his colleagues for his after Business hours "Board of Education" meetings in hideaway offices in the House. During these off-the-record sessions, the Speaker and powerful committee chairmen would gather for poker, bourbon, and a frank discussion of politics. Rayburn alone determined who received an invitation to these gatherings; to be invited to even one was a high honor. On April 12, 1945, Vice President Harry Truman, a regular attendee since his Senate days, had just arrived at the "Board of Education" when he received a phone call telling him to immediately come to the White House, where he learned that Franklin D. Roosevelt was dead and he was now President of the United States.

For the next 21 years, Rayburn was the leader of the House Democrats. His career as Speaker was interrupted twice: 1947–1949 and 1953–1955, when Republicans controlled the House. During those periods of Republican rule, Rayburn served as Minority Leader. However, he so disliked the term "minority leader" that he asked to be referred to as the "Democratic Leader" during those interim four years when the office of Speaker was held by the Republican Joseph W. Martin Jr. of Massachusetts, actually a close personal friend of Rayburn's.

In 1956, Rayburn was baptized by Elder H. G. Ball in the Primitive Baptist Church, also known as Old Line Baptist or Hard Shell Baptist Church.

In 1957 Rayburn dedicated the Sam Rayburn Library and Museum in Bonham in the style of a presidential library to preserve his memory, library collection, honors, and mementos.

Also, as Speaker of the House, Rayburn forged close friendships and partnerships with legislatures of emerging independent countries and democracies on the continent of Africa, especially Nigeria, a rising political power on that continent. Rayburn was a good friend of Jaja Wachuku, the first indigenous Speaker of the Nigerian House of Representatives, from 1959 to 1960.

Rayburn died of cancer in 1961 at the age of 79 and was posthumously awarded the Congressional Gold Medal. By the time of his death, he had served as Speaker for nearly twice as long as any of his predecessors.

In 2016 the Plano Star Courier published a story about an article in the October 2016 issue of Southwestern Historical Quarterly (a scholarly journal published by the Texas State Historical Association) profiling Sam Rayburn's "lady friend" who was a woman named Margaret Fallon (Peggy) Palmer, the widow of former U.S. Attorney General A. Mitchell Palmer, and her close relationship with Rayburn.