Born to a Maori mother (Desrae Hughes) and an English-Australian father (Tim Castle), Keisha was four years old when her family moved to New Zealand. Her parents later separated. Originally an Australian citizen, she became a New Zealand citizen in 2001 (losing her Australian citizenship under the now repealed S17 of the Australian Citizenship Act). She is the eldest of four children.

On January 27, 2004, she became the youngest person ever nominated for the Academy Awards' Oscar for Best Actress, for her portrayal of Paikea Apirana (Pai) in the independent film Whale Rider. Despite not possessing any previous acting experience, the then 11-year-old Keisha went directly from her Auckland classroom to the set when the film began shooting in New Zealand in 2002. She received widespread critical acclaim and an Academy Award for Best Actress nomination for her performance. She followed this up by appearing in Prince's controversial music video for his song Cinnamon Girl. She has also appeared in Vanity Fair magazine.

Her most recent film role was as Queen Apailana in Star Wars Episode III: Revenge of the Sith. Her upcoming roles include the Virgin Mary in Nativity (filming from May 2006), and Sunni in Hey, Hey, It's Esther Blueburger (filming from October 2006).