Wyeth is one of the best-known American painters of the 20th century. At the age of twenty, he had his first one-man exhibition at the William Macbeth Gallery in New York. He also exhibited at the Art Institute of Chicago.  In 1943, he participated in a group show at the Museum of Modern Art in New York that presented "American Realists and Magic Realists."  He exhibited at the Pennsylvania Academy of the Fine Arts in 1947, and in 1966 where 200 of his paintings were on display.  In June of 1960, the Royal Academy in London, England, held its first Andrew Wyeth retrospective exhibition, "The Two Worlds of Andrew Wyeth." In 1976, the exhibition came to the Metropolitan Museum of Art in New York

Wyeth was a recipient of many awards from many institutions and societies, including the Pennsylvania Academy of the Fine Arts, Carnegie Institute, the Wilmington Museum, the Butler Art Institute, the American Academy & Institute of Arts (1947); the American Watercolor Society (1952); as well as many others. President John F. Kennedy nominated Wyeth for the Medal of Freedom and President Lyndon B. Johnson presented it to him in 1963. In 1990, President George Bush awarded him the Congressional Medal.

The artist's work is in many private and public collections, among them the Metropolitan Museum of Art, New York; the Museum of Fine Arts, Boston; the Art Institute of Chicago; the National Gallery of Art, Washington, D.C.; the University of Nebraska; New Britain Museum, and the Delaware Trust Bank.