He was born on Analostan Island in Fairfax County, Va., and was a graduate of the University of Pennsylvania (1818), receiving a law degree from the College of William and Mary in 1820.

He practiced law in Virginia and was a delegate to the Virginia constitutional convention in 1829, and a member of the State house of delegates. A Jackson Democrat, he was elected to the Twenty-fifth United States Congress in 1836.

In 1847 he was elected to the Senate after the death of Isaac S. Pennybacker, and was reelected in 1850 and 1856. Mason represented the majority view in leading the Senate committee which investigated the John Brown (abolitionist) raid on Harper's Ferry of October 1859. (Thus the document published as the U.S. Congress, Senate Select Commission on the Harper's Ferry Invasion (June 15, 1860) is often referred to as the Mason Report.) Mason was President pro tempore of the Senate during the Thirty-fourth and Thirty-fifth Congresses but was expelled from the Senate in 1861 for support of the Confederacy.

While traveling to his post as Confederate envoy to Britain and France, on the British mail steamer RMS Trent, the ship was stopped by USS San Jacinto on November 8, 1861. Mason and John Slidell were confined in Fort Warren, Boston Harbor, precipitating the Trent Affair that threatened to bring Britain into open war with the United States of America. He was released in January 1862 and proceeded to London, where he represented the Confederacy until April 1865.

Until 1868 he lived in Canada, and then returned to Virginia. He died near Alexandria, Va. on April 28, 1871 and was interred in Christ Church Episcopal Cemetery, Alexandria, Va.

One sister was the wife of Confederate General Adjutant Samuel Cooper (general). One sister was the wife of Sidney Smith Lee-son of Henry Lee; they were the parents of Confederate Major General and Virginia Governor Fitzhugh Lee.