Nena von Schlebrügge was born in Mexico City, Mexico. She is the daughter of a Swedish mother, Birgit Holmquist (1911–1973), and a German father, Colonel Baron Friedrich Karl Johannes von Schlebrügge (1886–1954), a German monarchist and cavalry officer in World War I who became a businessman during the 1920s and 1930s in Berlin. During World War II, he was jailed by the National Socialists for refusing to rejoin the military and for protecting Jewish friends. Birgit Holmquist married him in jail and used her Swedish national privilege to get him out; the couple fled to Mexico, where Nena and her brother Björn were born.

Von Schlebrügge's maternal grandmother's parents were German and Danish. Her mother had served as se:Axel Ebbe's model for Famntaget ("The Embrace"), a 1930s statue of a nude woman that overlooks the harbor of Smygehuk in Sweden. On her father's side, she has an older half-sister, who was the paternal grandmother of German-Swedish football player Max von Schlebrügge.

In 1955 at the age of 14, Nena was discovered by Vogue Photographer Norman Parkinson when he was on a tour in Stockholm, Sweden. In 1957, Nena moved to London, England, to pursue a career in high-fashion modeling. She found immediate success and was invited to come to New York City by Eileen Ford of the Ford Modeling Agency to continue her modelling career.

In the snow storm of March 1958, at the age of 17, she arrived in New York City on the Queen Mary. In New York City, she continued her career as a top model, working at Vogue and Harper's Bazaar. She was photographed by many fashion Photographers, including Gleb Derujinsky.

Nena married Timothy Leary in 1964 at the Hitchcock Estate (commonly known as "Millbrook"). D. A. Pennebaker documented the event in his short film You're Nobody Till Somebody Loves You. Charles Mingus played piano at the wedding ceremony. The marriage lasted a year before von Schlebrügge divorced Leary in 1965. In 1967 she married Indo-Tibetan Buddhist scholar and ex-monk Robert Thurman, whom she had met at Millbrook. In the same year, Nena and Robert's first child, Ganden Thurman, was born. In 1970, Robert and Nena's second child, Uma Thurman, was born. They have two more sons: Dechen (b. 1973) and Mipam (b. 1978). The children grew up in Woodstock, NY, where the Thurmans had bought nine acres of land with a small inheritance Nena had received. The Thurmans built their own house there. In addition to their four children, the pair has seven grandchildren.

In 1967, she had a part in the Edie Sedgwick film Ciao! Manhattan. The film took four years to make; and drastic changes from the original story were made, causing the filmmakers to remove many scenes, including Nena's, shot in 1967. These deleted scenes can be found on the DVD version.

From 1987 to 1989, Nena was the Program Director at the New York Open Center and, from 1991 to 2002, was the Managing Director of Tibet House U.S. located in New York City. The Tibet House had been founded in 1986 by the Thurmans, Philip Glass, and Richard Gere, at the behest of the Dalai Lama. Nena oversaw the construction of Tibet House, the educational programming, and, with Philip Glass, initiated the annual benefit concert at Carnegie Hall, as well as the annual benefit auction at Christie's.

Since 2001, Nena has been the Managing Director of the Tibet House-owned Menla Mountain Retreat, where she has overseen the construction of a state-of-the-art Tibetan medicinal spa facility and Business in the Catskill Mountains in Phoenicia, New York. She is also a psychotherapist.