With the outbreak of the Quasi-War with France, Talbot was re-commissioned as a captain in the United States Navy on May 11, 1798. He served as commander of from June 5, 1799 until September 8, 1801, sailing it to the West Indies where he protected American commerce from French privateers during the Quasi-War. He commanded the Santo Domingo Station in 1799 and 1800 and was commended by the Secretary of the Navy for protecting American commerce and for laying the foundation of a permanent trade with that country. It is said that Talbot was wounded 13 times and carried 5 bullets in his body.