In 1785, Greenup was elected to represent Fayette County for a single term in the Virginia House of Delegates. During his service, he was appointed to a committee with Benjamin Logan and James Garrard to make recommendations on ways to further divide the area that would become Kentucky. The committee was also responsible for revising acts and surveys related to land and water surveys in the area. The committee ultimately recommended the creation of three new counties – Bourbon, Madison, and Mercer. When Mercer County was created later that year, Greenup was appointed a justice there. In 1786, Greenup served as a quartermaster in Benjamin Logan’s expedition against the Shawnees in the Ohio country. During this time, Greenup continued to practice law in Fayette County and pursued various other interests. He was a founding member of the Danville Political Club and in 1787, he joined the Kentucky Society for Promoting Useful Knowledge. Future Kentucky Governors Isaac Shelby and James Garrard, as well as future Supreme Court justice Thomas Todd were also members of the Society. In 1789, he helped organize the Kentucky Manufacturing Society. Later, he was appointed to the Kentucky River Company, a group dedicated to improving infrastructure on the Kentucky River. On July 9, 1787, during a brief return to Virginia, Greenup married Mary Catherine ("Cathy") Pope of Hanover County, Virginia; the couple had two children – Nancy and William. Political career in Kentucky Greenup served as clerk of the first Kentucky statehood convention in Danville in 1784. He was elected as a delegate to the second and sixth statehood conventions in 1785 and 1788, respectively, and was a trustee of the city of Danville in 1787. H.E. Everman, biographer of fellow delegate James Garrard, noted that despite Greenup's excellent legal background and legislative experience, his lack of oratorical skills prevented him from taking more of a leadership role in the conventions. When Kentucky was admitted to the Union in 1792, Greenup moved to Frankfort where he was rewarded for his efforts on behalf of the state by being chosen as an elector for the state's senators and governor. He also served in the first Kentucky Senate. Following this, he was appointed to the court of oyer and terminer, but resigned immediately to accept a seat in the U.S. House of Representatives. He was one of Kentucky's first two representatives in the House, and was elected to three