The name refers to the Lakota name: wa sa wak pa'la (red stream).

Home to the University of South Dakota, Vermillion has a mixed academic and rural character: the university is a major academic institution for the state, with its only law and medical schools and its only AACSB-accredited business school.

Lewis and Clark camped at the mouth of the Vermillion River near the present-day town on August 24, 1804.

In May 1843, John James Audubon visited the Vermillion ravine to view the bird life.

The town was considered for the site of South Dakota's first mental institution (now the Human Services Center) in 1873, but the hospital was eventually awarded to nearby Yankton.

The original town was entirely below the bluffs on the banks of the Missouri River, and three-quarters of it washed away in the Great Flood of 1881.

Along with Eugene Chafin, they toured South Dakota by train, including stops in Mitchell, Tripp, Yankton, and Elk Point.

[10] According to the United States Census Bureau, the city has an area of 4.03 square miles (10.44 km2), all land.

The Mayor is elected at-large and presides over City Council meetings.

With the consent of the City Council, the mayor appoints individuals to serve on the Library Board and Planning Commission.

The Planning Commission serves a vital role in recommending major policy changes to the governing body for the development of the community.

[18] Prentis Park includes a new swimming pool opened in 2017, with a waterslide, diving board, shallow play area, "lazy river", and snack bar.

The baseball field is currently home of the Vermillion High School, Post 1 American Legion, University of South Dakota club, and VFW teams.

Its collections include fossils, botanical and biological specimens, and cultural items related to the history of inhabitants of South Dakota and the Upper Northern Plains.

Built five years prior to South Dakota statehood, this house is one of the few surviving 19th century structures in the vicinity of Vermillion.

Inkpa Mani (Javier Lara-Ruiz[27]) led group discussions to help create imagery taken from Native American creation stories.

[26][28] Ratingen in the German state of North Rhine-Westphalia has been Vermillion's sister city since 1969.