Sophia Bush, an only child, was born and raised in Pasadena, California to Charles William Bush, who is an advertising and celebrity photographer working in the United States today, and Maureen, a photography studio manager. She attended Westridge School for Girls (Pasadena) and the University of Southern California and was a member of the Kappa Kappa Gamma sorority, where she served as Social Chair. Bush attended USC for three years before getting the role of Brooke Davis on One Tree Hill (2003). In 2000, she was the Tournament of Roses Parade Queen. Bush is of French-Canadian and Italian ancestry.

Bush made her first big screen appearance in the comedy Van Wilder as Sally. Since then, she has made appearances in several television shows including Nip/Tuck, Sabrina, the Teenage Witch, and Punk'd. She was cast as Kate Brewster in Terminator 3: Rise of the Machines, but was replaced by Claire Danes, as the director thought she was too young. In 2003, she won the role of Brooke Davis in the television series One Tree Hill. The show is one of The CW network's biggest hits and is exported all around the world. In between working on One Tree Hill, Bush has been cast in several films, such as Supercross, Stay Alive, John Tucker Must Die, and a remake of The Hitcher. Bush received a "Rising Star" award at Vail Film Festival for her work in The Hitcher. She won 3 Teen Choice Awards for her work in John Tucker Must Die and The Hitcher. On April 20, 2007, it was confirmed that Bush will star in Francois Velle's "The Narrows" with Kevin Zegers, Eddie Cahill and Vincent D'Onofrio. It is reported that she will play the beautiful, intelligent and self-assured 'Kathy Popovich'. Filming began in New York on April 24, 2007 and is due for a 2008 release date.

On April 16, 2005, Bush married actor Chad Michael Murray, her One Tree Hill co-star. They dated for almost two years before they were married in Santa Monica. But then they announced their separation on September 26, 2005 after five months of marriage. In December of 2006, Bush and Murray's divorce was made final. Bush was in a relationship with Stay Alive co-star Jon Foster after her divorce until August 2007. Later, rumors surfaced that Bush and Dallas Cowboys Quarterback Tony Romo were dating. They were reportedly seen together in Texas. In December 2007, it was reported by Rush & Molloy in the New York Daily News that Bush has "now hooked up with co-star James Lafferty"; the report also mentioned that a rep for the actress has denied there is any romance.