In 1999, Murray moved to Hollywood where he supported himself modeling for such clients as Skechers, Tommy Hilfiger and Gucci. Then he was cast in the role of rich brat, Tristin DuGray on Gilmore Girls; which was one of the main characters in the first season of the series and then became a recurring character thereafter. He appeared in several guest starring television roles, including an episode of Undressed and an episode of Diagnosis: Murder. Murray portrayed the role Charlie Todd on the successful television series Dawson's Creek in 2001. In 2003, he appeared in television film, Aftermath: A Long Way Home. Murray then appeared in the Walt Disney Pictures feature film, Freaky Friday alongside Lindsay Lohan and Jamie Lee Curtis. The film was a major box office success, earning a total of $110,222,438 in the United States alone. Critics were mostly positive in their reviews of the film, and the film garnered a "B" grade on Yahoo! Movies and an 88% "Certified Fresh" approval rating on Rotten Tomatoes. Murray also appeared in the television film The Lone Ranger where he portrayed the role of Luke Hartman.
Popular among teenagers and young adults in the early 2000s, he has been featured on the covers of numerous magazines, including People, Vanity Fair and Entertainment Weekly.
Later in the year of 2003, Murray won the main role of Lucas Scott in the successful WB television series One Tree Hill. The series quickly became the channel's biggest hit with over 4.50 million viewers on the first season's finale. The series was The WB's most successful and top rated television program when it first aired in 2003 and continued receiving top ratings for The CW. The series also earned Murray numerous awards, including two Teen Choice Awards, and spawned a book series. After Murray gained mainstream fame and media exposure, he also became a spokesperson for several high-profile deals. He and his One Tree Hill co-stars were the official endorsers for MasterCard and K-Mart. They endorsed Cingular Wireless and the Chevy Cobalt.
Following Murray's starring role on One Tree Hill, he appeared on the cover of several mainstream magazines such as Rolling Stone and People. That same year, he was voted as one of "TV's Sexiest Guys" in People magazine. In 2004, Murray starred in the romantic comedy A Cinderella Story with Hilary Duff. Though the reviews were mostly negative, the film went on to become a moderate box office success, earning $70.1 million worldwide. The film led to 2005 Teen Choice Awards wins in several categories. Later that year, Murray appeared on the cover of Teen People magazine.
Following his separation from Bush, Murray began dating Kenzie Dalton, whom he met in 2005 when Dalton, a first runner-up in the 2005 Miss North Carolina Teen USA pageant, was an extra on One Tree Hill. They became engaged in April 2006, but in August 2013, they called off their seven-year engagement. Murray dated his Left Behind co-star Nicky Whelan from October 2013 to May 2014.
In 2010, Murray played Alicia Keys's love interest in her music video for "Un-Thinkable (I'm Ready)". Then he played Ethan McAllister in Lifetime's TV movie Lies in Plain Sight. Murray also co-starred in Christmas Cupid with Ashley Benson and Christina Milian. The film is an ABC Family Original Movie and is "about a comatose girl who visits her Christmas past, present, and future".
Murray released a novel in September 2011, titled Everlast. In 2017, he published American Drifter: An Exhilarating Tale of Love and Murder, which he coauthored with Heather Graham. The romantic-thriller was inspired by a dream.
In 2011, The CW announced he would return for a guest appearance as Lucas Scott in the final season of One Tree Hill. The episode aired on February 22, 2012. In 2013, Murray appeared in Fruitvale Station, a film chronicling the last day of Oscar Grant, who was killed by a police officer at a BART station. The film won two major awards at the 2013 Sundance Film Festival.
In August 2014, he was cast in a featured role as Agent Jack Thompson for Marvel's television series Agent Carter, and has returned for the second season.
Later in 2014, Murray began dating his Chosen co-star Sarah Roemer. In January 2015, it was announced that he and Roemer had married, and were expecting their first child. They announced that Roemer gave birth to their son on May 31, 2015. In November 2016, they announced that they were expecting their second child. Their second child, a daughter, was born in March 2017.
