Ederle early became an avid swimmer. She was a leading exponent of the eight-beat crawl (eight kicks for each full arm stroke) and between 1921 and 1925 held 29 national and world amateur swimming records. In 1922 she broke seven records in a single afternoon at Brighton Beach, N.Y. At the 1924 Olympic Games in Paris she was a member of the U.S. team that won a gold medal in the 4 × 100-metre freestyle relay. She also captured bronze medals in the 100-metre and 400-metre freestyle events.

In 1925 Ederle made an unsuccessful attempt to swim the English Channel, but the following year she returned to France to try again. In the face of widespread doubt that a woman could accomplish the feat, she set out from Cape Gris-Nez near Calais, France, on August 6 and swam the 35 miles (56 km) to Dover, Kent, Eng., in 14 hours 31 minutes, beating the men's world record by 1 hour 59 minutes. Ederle was greeted on her return to New York City by a ticker-tape parade, and she toured for a time as a professional swimmer. A series of misfortunes, culminating in a serious back injury in 1933, ended her public career for a time, but in 1939 she appeared in Billy Rose's Aquacade at the New York World's Fair.

Ederle, whose hearing was permanently impaired while achieving her English Channel triumph, later became a swimming instructor for deaf children. She was inducted into the International Swimming Hall of Fame in 1965 and the Women's Sports Hall of Fame in 1980.