His youngest brother Nathaniel would also become a lawyer, but continued the family's westward migration by first establishing a legal practice in the Missouri Territory before moving slightly east and holding various positions in the Illinois Territory and ultimately becoming U.S. District Judge for District of Illinois.

His birth family included several sisters who survived to adulthood and married, including Penelope Edwards Oldham (1769–1821), Jane Pope Field (1772–1852; also born in Fauquier County) and Hester Pope Edwards (1788–1868; born in Louisville).

He received a private education appropriate to his class, including at Salem Academy in Bardstown, Kentucky.

His vote against the War of 1812 made since he leaned toward the Federalist Party at that time, but political gossip attributed this unpopular political stance to his wife's influence (Eliza Johnson Pope was daughter of an Englishwoman, Catherine Nuth, wife of Joshua Johnson, and she had spent much of her youth in England).

He and his wife returned to live in Lexington, Kentucky where he practiced law and taught at Transylvania University.

During his term as governor he arranged for the construction of the Old State House by the Kentucky architect Gideon Shryock.

During this time, and primarily under the advisement of his wife Eliza, Pope built the avant-garde mansion in what was then on the edges of the "Athens of the West" Lexington, Kentucky.

[9] After his marriage, Pope lived in his wife's home, Walton Manor, and practiced law from the older brick cottage in front of the mansion.

Pope Villa of Lexington, Kentucky was built by Benjamin Latrobe for him and his wife Eliza.