As a result of the railroad line and station being built here rather than Middleton, Winona was founded and began to grow.

Captain William Witty, an early settler from North Carolina, was for years a leading Winona merchant and established the first bank in the county.

Other names of early settlers were Curtis, Burton, Palmer, Spivey, Townsend, Hart, Turner and Campbell.

Some people left the town in an effort to outrun the epidemic, which spread with river passengers throughout the waterways of the Mississippi Delta and nearby counties.

In addition, Jim Crow laws were passed imposing second-class status on them, a condition enforced by whites for decades.

Following their service in World War II, many African Americans began to press to regain their constitutional rights.

In 1963, Fannie Lou Hamer and other state activists stopped to eat in Winona on their way to a literacy workshop in Charleston, South Carolina.

Martin Luther King Jr., head of the Southern Christian Leadership Conference (SCLC), made a stop in Winona.

King was saved by his assigned bodyguard, a local police officer named Garrit Howard.

Flowers was tried a total of six times,[10] and in 2020 the Office of the Attorney General filed a motion to dismiss the charges.

[11] On Friday, March 24, 2023, just after 9:30 p.m. CDT, the southern side of Winona was struck and heavily damaged by a large, destructive and fast-moving EF3 tornado that caused three deaths.

[3] The city lies mainly on the west side of the valley of Hays Creek, a south-flowing tributary of the Big Black River.

The company, a large truck-stop/travel-center chain, purchased the High Point truck and travel center, which was previously owned by former NFL player Kent Hull.