Nuyen was born in Marseille, Bouches-du-Rhône, Provence-Alpes-Côte d'Azur, France. Her mother was French, her father Vietnamese. During World War II, her mother and grandfather were persecuted by the Nazis for being Gypsies. Nuyen was raised in Marseille by a cousin she calls "an orchidaceae raiser who was the only person who gave a damn about me".

In 1955, while working as a seamstress, Nguyen was discovered on the beach by Life magazine photographer Philippe Halsman. She then became a stage actress and played the lead in the 1958 theatrical production of The World of Suzie Wong, opposite William Shatner. (She later worked with Shatner in an episode of Star Trek, as the memorable Elaan of Troyius, and an episode of Kung Fu.) Her distinctive accent made her recognizable to television audiences. She was originally cast to star in the film production, but was replaced by Nancy Kwan.

Nuyen appeared on television and in films, including South Pacific (1958), Satan Never Sleeps (1962), A Girl Named Tamiko (with Laurence Harvey) (1962), Diamond Head (1963), Dimension 5 (1966), Battle for the Planet of the Apes (1973), and The Joy Luck Club (1993). She continues to appear in films and recently appeared in the film The American Standards (2007). In 1978, Nuyen guest starred with Peter Falk and Louis Jourdan in the Columbo episode Murder Under Glass. In 1986, she joined the cast of St. Elsewhere as Dr. Paulette Kiem, remaining until the series ended in 1988.

From 1963 to 1966, Nguyen was married to Dr. Thomas Gaspar Morell, a psychiatrist, by whom she has a daughter Fleur, who resides in Canada and works as a film makeup artist. She met her second husband, Robert Culp, while appearing on his show I Spy. They married in 1967 but divorced three years later. Nuyen and Culp were to appear as co-hosts of the second episode of the TV series Turn-On in 1969, but the show was canceled after just one week.

In 1986, Nguyen earned a master's degree in Clinical psychology and began a second career as a psychological counselor for abused women and children, and women in prison. She received a Woman of the Year award in 1989 for her psychological work.