He served five terms as a U.S. congressman from Virginia's 2nd congressional district and later was important in Mississippi's development as a state.

He was generally successful in dealing with a variety of matters, including expansion, land policy, Indians, the War of 1812, and the constitutional convention of 1817 (of which he was elected president).

Often concerned with problems regarding West Florida, he had a significant role in 1810 in negotiations that led to the peaceful occupation by the United States of part of that territory.

McCain (1967) concludes that Holmes's success was not based on brilliance but upon kindness, unselfishness, persuasiveness, courage, honesty, diplomacy, and intelligence.

He also organized the land east of the Pearl River, which the Choctaw people had ceded to the United States under considerable pressure.

He was predeceased by his brother, Major Andrew Hunter Holmes, a casualty of the Battle of Mackinac Island during the War of 1812.

[5] Holmes Avenue in Huntsville, Alabama was part of the Mississippi Territory when built and is named in honor of him.