The school was founded in 1848 by Godwin Cotton Moore as a four-year women's college, an unusual investment for a small river town in antebellum North Carolina. It traces its roots a little earlier still, to Hertford Academy. The McDowell Columns building, raised in 1851 to house classrooms and dormitories, still serves as the administrative center. The name shifted in those first decades - Chowan Female Collegiate Institute for a while, then back to Chowan Baptist Female Institute - but the mission stayed the same: educate women in a region where such schools were rare. The Civil War tested the institute, but it survived. In 1910 it took the name Chowan College and began awarding bachelor's degrees. In 1931, eighty-three years after its founding, it began admitting men.

The school takes its name from the Chowanoke people, the Algonquian polity that lived in what is now Murfreesboro and the surrounding counties at the time of English contact in the 1580s. The name appears in the journals of Walter Raleigh's scouts. The Chowanoke were dispossessed of most of their land through war and treaty in the late seventeenth and eighteenth centuries; by the time the institute opened in 1848, few of the indigenous people for whom the river was named remained in the area. The school's adoption of the name was, in the language of the period, a tribute - though the relationship between such tributes and the actual histories of dispossession deserves more thought than the founders gave it. The original school mascot, the Braves, was changed in 2006 to the Hawks to comply with NCAA policy on Native American mascots.

The Great Depression nearly broke the school. Financial pressures forced Chowan to reorganize as a two-year junior college in 1937. It remained a junior college for fifty-five years - through World War II, through the postwar GI Bill expansion, through the civil rights era. In 1992 it returned to four-year status, admitting a junior class for the first time in more than half a century. On April 6, 2006, the board of trustees voted to rename the institution Chowan University, with the change taking effect that September. A year later the university, alongside four other private Christian schools in North Carolina - Mars Hill, Campbell, Wingate, and Gardner-Webb - negotiated greater autonomy from the Baptist State Convention of North Carolina. The convention agreed to direct its support to a scholarship fund for Baptist students rather than to the schools directly. Two years after that, the universities formally separated from the convention's governance, while keeping what both sides called a 'good faith and cooperative' relationship.

Chowan's athletic teams compete in NCAA Division II as the Hawks, primarily in Conference Carolinas, with football, basketball, baseball, soccer, and a long list of other sports including women's bowling and acrobatic and tumbling. The university has produced an unusual number of NFL players for a school its size - Fred Banks, Robert Brown, George Koonce, Mark Royals, Jody Schulz, Curtis Whitley, among others. It has also produced quieter distinctions: Lucy Henderson Owen Robertson, a graduate of the institute's early years, became the first woman to serve as president of a college in the American South. In December 2023, Rosemary M. Thomas was named Chowan's 24th president and the first woman to hold the office; she took up the role on March 11, 2024. The campus sits along the small streets of Murfreesboro, in Hertford County, about an hour from any large city - the kind of place where a 178-year-old institution can keep going, generation after generation, without making much noise about it.