Colonel James Poage, a veteran of the American Revolution, arrived in the free state of Ohio from Staunton, Virginia in 1804 to claim the he had been granted in what was called the Virginia Military District. Poage was among a large group of veterans who received land grants in what was first organized as the Northwest Territory north of the Ohio River for their service in the American Revolutionary War, and freed their slaves when they settled there. Poage and his family laid out the town of Staunton in 1812; it was renamed in 1816 to honor General Eleazar Wheelock Ripley, an American officer of the War of 1812.
Given its location on the river, Ripley became a destination for slaves escaping from slavery in Kentucky on the other side. Both black and white residents developed a network, making Ripley an early stop on the Underground Railroad, to help slaves escape North to freedom. A number of prominent abolitionists lived in the town in the 19th century, mainly on Front Street near the river, including John Rankin, former slave John Parker, Thomas McCague, Thomas Collins and Dr. Alexander Campbell.
Rankin moved from Kentucky to Ripley in 1822 and later built a house on Liberty Hill overlooking the town, the river and the Kentucky shore. From there, he signaled escaping slaves with a lantern on a flagpole  and provided them shelter. (It is now known as the John Rankin House (Ripley, Ohio), and has been designated as a National Historic Landmark.) The account of Margaret Garner, a slave woman who escaped across the frozen river to Ripley in 1838 and stayed in Rankin's house, inspired the character of Eliza in Harriet Beecher Stowe's landmark book, Uncle Tom's Cabin (1852). The bestselling book of the nineteenth century, it aroused controversy and strengthened the abolitionist movement. Rankin was the minister at the Ripley Presbyterian Church for twenty-four years.