Portsmouth is a city in Scioto County, Ohio, United States, and its county seat. Located in southern Ohio 41 miles (66 km) south of Chillicothe, it lies on the north bank of the Ohio River, across from Kentucky and just east of the mouth of the Scioto River. The population was 18,252 at the 2020 census. It is the principal city of the Portsmouth micropolitan area.

The area was occupied by Native Americans as early as 100 BC, as indicated by the Portsmouth Earthworks, a ceremonial center built by the Ohio Hopewell culture between 100 and 500 AD.

According to early 20th-century historian Charles Augustus Hanna, a Shawnee village was founded at the site of modern-day Portsmouth in late 1758, following the abandonment of Lower Shawneetown.

European-Americans began to settle in the 1790s after the American Revolutionary War, and the small town of Alexandria was founded. Located at the confluence, Alexandria was flooded numerous times by the Ohio and the Scioto rivers.

In 1796, Emanuel Traxler became the first person of European descent to permanently occupy land in what would later be known as Portsmouth, after the United States gained its independence.

In 1803, Henry Massie found a better location slightly east and somewhat removed from the flood plains. He began to plot the new city by mapping the streets and distributing the land. Portsmouth was founded in 1803 and established as a city in 1815. It was designated as the county seat. Settlers left Alexandria, and it soon disappeared. Massie named Portsmouth after the town of Portsmouth, New Hampshire.

The Ohio state legislature passed "Black Laws" in 1804 that restricted movement of free blacks and required persons to carry papers, in an effort to dissuade blacks from settling in the state. These provisions were intermittently enforced by local governments and law enforcement, and sometimes used as an excuse to force African Americans out of settlements. In 1831, Portsmouth drove out African Americans from the city under this pretext. Many settled several miles north in what became known as Huston's Hollow, along the Scioto River. Its residents, especially Joseph Love and Dan Lucas, provided aid to refugee slaves in the following years and assisted them in moving north.

Although southern Ohio was dominated in number by anti-abolitionist settlers from the South, some whites also worked to improve conditions for blacks and aid refugee slaves. Portsmouth became important in the antebellum years as part of the Underground Railroad. Fugitive slaves from Kentucky and other parts of the South crossed the Ohio River here. Some found their future in Portsmouth; others moved north along the Scioto River to reach Detroit, Michigan, and get farther away from slave catchers. Many continued into Canada to secure their freedom. A historical marker near the Grant Bridge commemorates this period of Portsmouth's history. James Ashley of Portsmouth continued his activism and pursued a political career. After being elected to Congress, he wrote the Thirteenth Amendment to the United States Constitution, which abolished slavery in 1865 after the American Civil War.