Although the Pope family was well-established in Virginia, its members would only begin holding statewide office after the Revolutionary War, in which they supported the Patriot cause under the leadership of their neighbor, George Washington (whose distant ancestor John Washington had married the daughter of one of the earliest men named Nathaniel Pope.

His eldest brother John Pope (1770–1845) was born in Prince William County, Virginia and would also become a lawyer and hold high political office, including in both houses of the Kentucky legislature as well as the U.S. Congress before becoming governor of the Arkansas Territory.

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).

After a private education appropriate to his class, Nathaniel Pope attended Transylvania University, then read law in 1804.

Edwards, a lawyer and Maryland politician who had moved to Kentucky and then the Illinois Territory, was related to Pope's mother.

[5][1] Pope was instrumental both in securing the new territory's admission as the 21st State on December 3, 1818 (the statehood resolution passed regardless of the creative counting to achieve the former minimum of 60,000 persons) as well as in adjusting the new state's northern boundary from the southern extremity of Lake Michigan extending it north to the 42° 30' parallel.