He graduated from Mount Zion Academy and from South Carolina College at Columbia in 1820. He moved to Autauga County, Alabama, the same year, where he studied law and was admitted to the bar in 1823.
That same year he constructed a house ("Old Homestead") in the town of Lowndesboro, Alabama, twenty miles west of the state capitol in Montgomery. He was elected as a States Rights Democrat to the twenty-first and to the seven succeeding Congresses and served from March 4, 1829, to April 22, 1844, when he resigned the House to join the Senate. He served as chairman of the United States House Committee on Indian Affairs from 1831 to 1835.
He was nearly elected Speaker of the House in the 26th Congress, receiving 113 votes on the 8th ballot, just four votes short of the necessary 117 needed to be elected.
Robert M. T. Hunter was elected on the 11th ballot. In 1844 Lewis was appointed by his brother-in-law Governor Benjamin Fitzpatrick to the United States Senate to fill the vacancy caused by the resignation of William R. King in 1844.
He was reelected as the Democratic candidate in 1847 and served from April 22, 1844, until his death in New York City on October 25, 1848. In the Senate he served as chairman of the Finance Committee from 1845 to 1847.
A strikingly obese figure, Lewis was known to weigh as much as 500 pounds (227 kg), making him the heaviest member of Congress ever.
A specially-constructed seat was provided in the Senate chambers for him, and his carriage was fitted with unusually heavy suspension springs. Lewis is interred at Green-Wood Cemetery in Brooklyn, New New York
Member Alabama Legislature, 1826-1828. Member United States House of Representatives (Democrat) from Alabama, 21st-28th congresses, 1829-1844, chairman ways and means committee. Member United States Senate from Alabama, 1844-1848, states’ rights advocate, opposed high protective tariff and internal improvements by federal government, Chairman of Commission on finance.
Married Susan Elmore, March 11, 1823, 7 children.