De Varona became a household word among Olympic Games enthusiasts in 1960 when, at age 13, she became the youngest member of the U.S. swimming team at the Rome Olympics. Four years later, at the Tokyo Olympics, she won two gold medals—in the 400-metre individual medley and in the 4 × 100-metre freestyle relay—and by age 17 she had broken 18 world records in swimming.

After her Olympic triumph she retired from competition. Soon thereafter she was hired as a television commentator; she was the first woman to serve that function on network television. De Varona also became a vocal proponent of the principles ultimately embodied in Title IX legislation guaranteeing that no one shall because of sex be denied participation in any educational program (including sports programs at educational institutions) receiving direct federal aid. As a consultant to the Senate from 1976 to 1978, she also became involved with the legislative development of the U.S. Amateur Sports Act. Together with tennis great Billie Jean King (King, Billie Jean) and others, de Varona organized the Women's Sports Foundation. She served as that organization's first elected president (1976–84). De Varona graduated from the University of California at Los Angeles with a B.A. in political science in 1986.