Lewis was born in the small farming settlement of Freetown, Orange County, Virginia, the granddaughter of an emancipated slave who helped start the community. She was one of eight children.

She left Freetown at age 16, after her father died, and moved to Washington and eventually to New York City.. When she arrived in New York, an acquaintance found her a job in a Brooklyn laundry, where she was assigned to an ironing board. She had never ironed and lasted three hours before she was dismissed. She soon found work as a seamstress, and copied Christian Dior dresses for Dorcas Avedon, then the wife of Richard Avedon. She made a dress for Marilyn Monroe, as well as the African-inspired dresses for which she became well-known..

She also worked for the communist newspaper The Daily Worker, was involved in political demonstrations, and campaigned for Franklin D. Roosevelt..

In New York City, she married Steve Kingston, a retired merchant seaman and a communist. Shortly afterward, she met John Nicholson, an antiques dealer who in 1949 decided to open a restaurant on 58th Street, on the East Side of Manhattan. She became the cook, preparing cheese soufflés and roast chicken. Café Nicholson became an instant success among bohemians and artists. The restaurant was frequented by William Faulkner, Marlon Brando, Tennessee Williams, Truman Capote, Richard Avedon, Gloria Vanderbilt, Marlene Dietrich, and Diana Vreeland.. Lewis remained at the restaurant until the late 1950s. In the late 1960s, she broke her leg and was temporarily forced to stop cooking professionally. With encouragement from Judith Jones, the cookbook editor at Knopf who also edited Julia Child, she turned her handwritten pages into The Edna Lewis Cookbook (1972). This was followed by The Taste of Country Cooking in 1976. The book is considered a classic study of Southern cooking. In 1979, Craig Claiborne of The New York Times said the book "may well be the most entertaining regional cookbook in America"..

In 1949 Cafe Nicholson was located at ground level of a narrow brownstone building on the downtown side of 52nd Street between 2nd Avenue and 3rd Avenue. One entered on the right, directly into a passageway separated from the kitchen by a screenwall of dark wood with openings above shoulder height that gave a view of the narrow kitchen, roughly 12 feet by 16 feet, having two windows facing 52nd street, and not much wall space to arrange cooking facilities. Most frequently Edna Lewis would be there to look up with greetings, dressed in something dark, and often with an Indian Paisley wrapped round her shoulders.

At the end of the short passageway was the Dining Room, roughly 18 feet by 35 feet. On the right was a dark wood buffet topped with white marble, stacked high with white china plates, glassware, flatware and nappery interspersed with wire baskets loaded with lemons and other comestibles and a tub or two of highstanding palms. To the left were the small bare marble-topped cafe tables and bentwood or wire-framed chairs. A fine meal might begin with Mussels and herbed rice presented in their blue-blackshells on a white plate; then a perfectly roasted chicken, a simple salad of Boston Lettuce with a coating of lemon garlic dressing, and completed with a dark brown puff of chocolate soufflé, containers of whipped cream and molten chocolate offered at the side.

At the back of the dining room was a door leading out to the garden, a space of about 20 feet by 50 feet, furnished with more small tables and chairs similar to those seen inside. A famous photograph by Karl Bassinger shows the back of the brownstone with a group of young New Yorkers becoming world famous in their separate careers. Gore Vidal is believed to be the sole surviving member of the photograph.

Subsequently Cafe Nicholson moved to the studio located to the right of the on-ramp of the Queensboro Bridge on East 58th Street. For a time it was later located on the uptown side of 57th Street between Lexington Avenue and 3rd Avenue.

In a 1989 interview with The New York Times, Lewis said: "As a child in Virginia, I thought all food tasted delicious. After growing up, I didn't think food tasted the same, so it has been my lifelong effort to try and recapture those good flavors of the past."

After The Taste of Country Cooking was published, Lewis returned to restaurants, most notably to Gage and Tollner in Brooklyn. She worked there for five years before retiring in the mid-1990s. She co-founded the Society for the Revival and Preservation of Southern Food, a precursor to the Southern Foodways Alliance (SFA).

Lewis also lived and worked in Chapel Hill, North Carolina and Charleston, South Carolina. For example, from 1983 to 1984 she served as guest chef of The Fearrington House Restaurant located in Pittsboro, just outside Chapel Hill.

She introduced the chocolate soufflé dessert to the menu, and it has remained on the menu to this day. The dessert graced the cover of Gourmet magazine in 1983 and helped launch the Restaurant, then three years old.

She died peacefully in her sleep at her home in Decatur, Georgia in 2006, aged 89. She was sometimes called "the South's answer to Julia Child".