Thurman's mother, Nena Birgitte Caroline von Schlebrügge was a fashion model born in Mexico City, Mexico in 1941, to German Friedrich Karl Johannes von Schlebrügge, and Birgit Holmquist, from Trelleborg, Sweden. In 1930, Birgit Holmquist, Thurman's grandmother, modeled for a nude statue that stands overlooking the harbor of Smygehuk. Thurman's father, Robert Alexander Farrar Thurman, was born in New York City to Elizabeth Dean Farrar, a stage actress, and Beverly Reid Thurman, Jr., an Associated Press editor and U.N. translator. Thurman's mother was introduced to LSD guru Timothy Leary by Salvador Dalí; and married Leary in 1964; then wed Thurman's father in 1967.Thurman's father, Robert, a scholar and professor at Columbia University of Indo-Tibetan Buddhist studies, was the first westerner to be ordained as a Tibetan Buddhist monk. He gave his children a Buddhist upbringing: Uma is named after an Dbuma Chenpo (in Tibetan, "db" is silent; Mahamadhyamaka in Sanskrit, meaning "Great Middle Way") and pronounced /umə/ in General American, not /jumə/. She has three brothers, Ganden (b. 1971), Dechen (b. 1973) and Mipam (b. 1978), and a half-sister named Taya (b. 1960) from her father's previous marriage. She and her siblings spent time in Almora, India as children, and the Dalai Lama sometimes visited their home.

Thurman grew up mostly in Amherst, Massachusetts and Woodstock, New York. She is described as having been an awkward and introverted girl who was teased for her tall frame, angular bone structure, unusual name (sometimes using the name “Uma Karen” instead of her birth name) and size 11 feet (Thurman's large feet would later be filmed by Quentin Tarantino in the films he made with her). When she was 10 years old, a friend's mother suggested a nose job.

Thurman attended Northfield Mount Hermon, a college preparatory boarding school in Northfield, Massachusetts, where she was earned average grades, but excelled in acting. Talent scouts noticed her performance as Abigail in a production of The Crucible, and offered her the chance to act professionally. Thurman moved to New York City to pursue acting and to attend the Professional Children's School, but she dropped out before graduating.

• Eloise in Paris (2009) (pre-production) .... Nanny
• Motherhood (2009/I) (completed) .... Eliza Welsh
• Letters to Santa: A Muppets Christmas (2008) (TV) .... Joy
• My Zinc Bed (2008) (TV) .... Elsa
• Do Not Alter (2008)
• Welcome to Gattaca (2008) (V)
• The Accidental Husband (2008) .... Dr. Emma Lloyd
• The Life Before Her Eyes (2007) .... Diana McFee
• My Super Ex-Girlfriend (2006) .... Jenny Johnson / G-Girl
• The Producers (2005) .... Ulla
• Prime (2005) .... Rafi Gardet
• Be Cool (2005) .... Edie Athens
• Kill Bill: Vol. 2 (2004) .... Beatrix Kiddo - The Bride, 'Black Mamba'
  ... aka Kill Bill (USA: closing credits title)
  ... aka Kill Bill 2 (USA: informal title)
  ... aka Vol. 2 (USA)
• Paycheck (2003) .... Rachel