Upon returning to the United States in 1910, Thrasher came to Wilmington to study with Pyle and for a time shared a studio at 1305 Franklin Street with Eads Collins and Douglas Duer. When World War I interrupted his work, he served with the Fortieth Engineers, doing camouflage work in France along with Duer, with whom he had become close friends. Thrasher returned to Wilmington, married Janet Jackson of that city in 1920, and moved with her to New York City and Setauket, Long Island. They had one daughter, Audrey.

Thrasher was best known for his humorous covers done for the Saturday Evening Post and Liberty magazines. His first published cover was sold to the Saturday Evening Post in 1912 for $50.00. By 1926 he had contracted to do a cover a week for Liberty at $1,000.00 each. These covers constituted a series which depicted the life of a “Typical American Family,” in the words of Liberty’s editors. The model used for the likeness of the father was Thrasher. The story told by the covers was made in to a feature-length movie called For the Love of Lil. One of Thrasher’s most famous Post covers was done shortly before his death, published October 3,1936. It shows a butcher and a customer at opposite sides of a scale which is weighing a chicken; each is pushing the scale in a different direction. Norman Rockwell recalled in Norman Rockwell: My Adventures as an Illustrator that people often wrote to him, mistakenly thinking this one of his covers. Rockwell goes on to express some rather uncomplimentary and condescending sentiments towards Thrasher, based on some incorrect facts, and one senses that a rivalry existed between the two artists. One also wonders whether, if Thrasher had lived longer, his reputation might not have ranked alongside Rockwell’s. In addition to covers, Thrasher did story illustrations and ads, some of which (Fisk Tire Co., Cream of Wheat Co. became quite well-known. These appeared in such magazines as Everybody’s, Collier’s, Red Book, Popular Magazine, and others.

His prodigious output was consistently lighthearted and painted in an accomplished style full of sparkle and vitality. Leslie Thrasher died on December 2,1936, several days after being rescued from his burning summer home, of pneumonia induced by smoke inhalation. Many items which could have shed light on his artistic career were also lost in the tragic fire. In honor of his friend, Douglas Duer named the next child born to him Leslie Thrasher Duer. The New York Times obituary stated: “Readers of the Saturday Evening Post will be especially shocked at the tragic death of Mr. Thrasher, for he had endeared himself to them by many cover pictures, full of character and homely American humor.”

Thrasher was a member of the Salmagundi Club.  The first exhibit of his work was held at State University, Farmingdale, NY, in 1973.