Cho's big break was a small role in the 1999 comedy American Pie, in which he popularised the slang term "MILF". His most successful starring role to date was as Harold Lee in 2004's Harold & Kumar Go to White Castle. Cho was one of the stars of the short-lived sitcom, Off Centre, and guest-starred on Charmed as a ghost. He was also a co-star of the now-defunct Fox sitcom Kitchen Confidential. Cho also had supporting roles in American Beauty, Evolution, and Down to Earth, and a minor role in Bowfinger.

In 2002, Cho had a starring role in the ensemble cast of Better Luck Tomorrow, a drama/dark comedy focusing on the travails of a group of Asian Americans living in Southern California who are academically successful, but socially discontented, and as a result engage in wantonly violent, criminal behavior. He was cast in NBC's new comedy The Singles Table September 2006, but the series never aired due to changes in scheduling and production. Cho was selected People Magazine's