David Holmes completed his legal education and began his legal practice in Harrisonburg, Virginia. He served as a U.S. Representative from Virginia's 2nd congressional district for over a decade. Appointed by President Thomas Jefferson, Holmes ended political factionalism in the Mississippi Territory and managed various state affairs, including land policy and Indian affairs. He played a pivotal role in the peaceful occupation of part of West Florida. Holmes was elected as the first governor of Mississippi, establishing the state's judicial system and organizing land ceded by the Choctaw people.

David Holmes’s political career reveals a unique blend of regional pragmatism and aggressive territorial expansionism. His approach to Indian affairs, marked by organizing land ceded by Native American tribes, juxtaposes economic development with displacement. Holmes’s role in the peaceful occupation of West Florida during the War of 1812 highlights a calculated strategy to secure regional dominance. His dual terms as governor and senator in Mississippi underscore a consistent focus on state governance and territorial organization, revealing a deeply localized yet expansionist vision.