Santiago was born on 17 May 1948 in the San Juan district of Villa Palmeras, Santurce, Puerto Rico. In 1961, she came to the United States when she was thirteen years old, the eldest in a family that would eventually include eleven children. Santiago attended New York City's Performing Arts High School, she and her husband, Frank Cantor, founded CANTOMEDIA, a film and media production company, which has won numerous awards for excellence in documentary filmmaking.

Her writing career evolved from her work as a producer/writer of documentary and educational films. Her essays and opinion pieces have appeared in national newspapers including the New York Times and the Boston Globe, and on mass market magazines like House & Garden, Metropolitan Home, and Good Housekeeping.

Upon publication of her first book, the memoir When I was Puerto Rican, Ms. Santiago was hailed as "a welcome new voice, full of passion and authority," by the Washington Post Book World.

Her first novel, America's Dream, has been published in six languages, and was an Alternate Selection of the Literary Guild. "Thrilling and page turning, the fabulous story of América Gonzalez is laid out masterfully," according to the Chicago Tribune.

Her second memoir, Almost a Woman, received numerous "Best of Year" mentions, in addition to an Alex Award from the American Library Association. It has recently been adapted into a film for Exxon Mobil Masterpiece Theatre, which premiered nationally on PBS on September 14, 2002.

With Joie Davidow, Ms. Santiago is coeditor of the anthologies, Las Christmas: Favorite Latino Authors Share Their Holiday Memories and Las Mamis: Favorite Latino Authors Remember their Mothers both published by Knopf.

Her 2004 memoir, The Turkish Lover, describes her life from the time she left New York in 1969 at age 21 until her graduation from Harvard in 1976, and focuses on her relationship with Turkish filmaker Ulvi Dogan.

While still in high school, she was cast in a small role in the 1967 film version of Bel Kaufman's novel, Up the Down Staircase where she portrayed a student named Esmeralda.

In addition to her literary endeavors, Ms. Santiago is an active volunteer. She is a spokesperson on behalf of public libraries. She has designed and developed community-based programs for adolescents, and was a founder of a shelter for battered women and their children. She serves on the boards of organizations devoted to the arts and to literature, and speaks vehemently about the need to encourage and support the artistic development of young people.

In addition to literary and community service awards, Ms. Santiago has earned a Master of Fine Arts in Fiction Writing from Sarah Lawrence College and Honorary Doctor of Letters from Trinity College and from Pace University.