The founder, Vernon Rudolph, worked for his uncle, Ishmael Armstrong, who purchased a secret recipe for yeast-raised doughnuts and a shop on Broad Street in Paducah, Kentucky, from Joseph LeBeouf of Lake Charles, Louisiana. Rudolph began selling the yeast doughnuts in Paducah and delivered them on his bicycle. The operation was moved to Nashville, Tennessee, and other family members joined to meet the customer demand. Rudolph sold his interest in the Nashville store and in 1937 opened a doughnut shop in Winston-Salem, and began selling to groceries and then directly to individual customers. The first Krispy Kreme store was located in a rented building on South Main Street in Winston-Salem in what is now called historic Old Salem.

By the 1960s, Krispy Kreme was well-known throughout the southeastern United States, and it began to expand into other areas of the country.

In 1976, Krispy Kreme Doughnut Corporation became a wholly owned subsidiary of Beatrice Foods of Chicago, Illinois. The headquarters for Krispy Kreme remained in Winston-Salem. A group of franchisees purchased the corporation back from Beatrice Foods in 1982. A location in Eden Prarie, closed as of February 21, 2008, along with all Minnesota locations

On June 3, 2005, National Doughnut Day in the US, participating franchises gave away free doughnuts.

On February 19, 2007, Krispy Kreme began selling the Whole Wheat Glazed doughnut in an attempt to appeal to the health conscious. The doughnut has twenty kilocalories (83,736 J) fewer than the original glazed (180 vs. 200 kcal) and contains more fiber (2 grams vs. 0.5 grams). As of January 2008, Krispy Kreme doughnuts are free of trans fats and are labeled as "0 grams of trans fat".