Rossellini was born in Rome, the daughter of Swedish actress Ingrid Bergman, who was of Swedish and German descent, and Italian director Roberto Rossellini, who was born in Rome from a family originally from Pisa, Tuscany. She has three siblings from her mother: her fraternal twin sister Isotta Ingrid Rossellini, who is an adjunct professor of Italian literature; a brother, Robertino Ingmar Rossellini; and a half-sister, Pia Lindström, who formerly worked on television and is from her mother's first marriage with Petter Lindström. She has four other siblings from her father's two other marriages: Romano (died at age nine), Renzo, Gil, and Raffaella.
Rossellini was raised in Rome, as well as in Santa Marinella and Paris. She underwent an operation for appendicitis at the age of five. At 11, she was diagnosed with scoliosis. In order to correct it, she had to undergo an 18-month ordeal of painful stretchings, body casts, and surgery on her spine using pieces of one of her shin bones. Consequently, she has permanent incision scars on her back and shin.
At 19, she went to New York City, where she attended Finch College, while working as a translator and a RAI television reporter. She also appeared intermittently on L'altra Domenica (The Other Sunday), a TV show featuring Roberto Benigni. However, she did not decide to stay full-time in New York until her marriage to Martin Scorsese (1979–1982), whom she met when she interviewed him for RAI.
At the age of 28, her modeling career began, when she was photographed by Bruce Weber for British Vogue and by Bill King for American Vogue. During her career, she has also worked with many other renowned photographers, including Richard Avedon, Steven Meisel, Helmut Newton, Peter Lindbergh, Norman Parkinson, Eve Arnold, Francesco Scavullo, Annie Leibovitz, Denis Piel, and Robert Mapplethorpe. Her image has appeared on such magazines as Marie Claire, Harper's Bazaar, Vanity Fair, and ELLE. In March 1988, an exhibition dedicated to photographs of her, called Portrait of a Woman, was held at the Musee d'Art Moderne in Paris.
Rossellini's modeling career led her into the world of cosmetics, when she became the exclusive spokesmodel for the international cosmetics brand Lancôme in 1982, replacing Nancy Dutiel in the United States and Carol Alt in Europe. At Lancôme, in 1990, she was involved in product development for the fragrance Trésor. In 1996, when she was 43, she was removed as the face of Lancôme for being "too old." In 2016, at the age of 63, she was rehired by Lancôme's new female CEO, Francoise Lehmann, as a global brand ambassador for the company.