In 2007, Westwick appeared in the film Son of Rambow and was cast as Chuck Bass in The CW's teen drama series Gossip Girl, based on the book series of the same name by Cecily von Ziegesar. Westwick said of his casting, "There wasn't much work in the UK. I was only in LA for a month and I got this show. It's changed my life." For his portrayal of Chuck, he assumed an American accent, based on the character Carlton Banks from The Fresh Prince of Bel-Air. As a result of the show's success, he was named one of 2008's Sexiest Men Alive by People magazine, and appeared the following year on its "100 Most Beautiful" list with the whole cast of Gossip Girl. Westwick earned the 2008 and 2009 awards for Best TV Villain at the Teen Choice Awards, and was named Breakthrough Talent by GQ in 2010. Entertainment Weekly also named Westwick's character Chuck Bass number one in their "Best Dressed TV Characters of 2008" list (tied with Leighton Meester's character Blair Waldorf), as well as in their "Best Performances" list alongside co-star Meester.
Westwick shared an apartment with his Gossip Girl co-star Chace Crawford in the Chelsea neighbourhood of Manhattan from the beginning of the series in 2007 until July 2009, when Crawford moved out. He was in a relationship with his Gossip Girl co-star Jessica Szohr and Jessica Serfaty.