Young Sophia was brought up in Pasadena; she made her acting debut in a school theater production while attending Westridge School for Girls, a small private school in her hometown. Sophia Bush was crowned the Queen of the Tournament of Roses at Pasadena Rose Parade in 2000; that same year she graduated from HS. In 2002 Sophia Bush made her screen debut as Sally, a college student, in the comedy Van Wilder (2002) opposite Ryan Reynolds. Sophia Bush attended University of Southern California for three years and took Journalism major and Theatre minor, albeit she did not graduate, taking her leave of absence after getting the part as Brooke Davis, a flirtatious cheerleader on the WB TV series One Tree Hill (2003). She was also cast to play opposite Arnold Schwarzenegger and Nick Stahl in Terminator 3 but, after she began principal photography on the film, the director deemed her too young for the role and she was soon replaced by actress Clare Danes.

However, Sophia Bush got her big break when 'One Tree Hill' developed a loyal following and became her steady gig over four seasons. It was while working on the series that Bush began dating her on-screen love interest, actor Chad Michael Murray. They wed in a seaside ceremony at the historic Casa del Mar Hotel in Santa Monica, California, in April 2005, but split after five months, in September 2005. She suffered from the traumatic experience and emotional pain of separation, while continuing her work on the series, now having a "professional relationship" with Murray and his new fiancée Kenzie Dalton. In February 2006, Sophia Bush filed petition to annul her brief marriage on the grounds of fraud; finally, she and Murray got divorced in December 2006. Meanwhile, she continued to land big screen roles, such as October Bantum in Stay Alive (2006), a horror film by writer/director William Brent Bell, and as Beth in John Tucker Must Die (2006), a comedy by director Betty Thomas. Sophia Bush is co-starring as Grace Andrews, who is terrorized by a killer played by Sean Bean, in the remake of The Hitcher (2007).