Cho, who is of Korean American descent, was raised in Knoxville and went into stand-up comedy in 1986.He attended University of Tennessee at Knoxville, and moved to Los Angeles, California in 1989 to pursue his career, but always with the intent of returning to his roots in Tennessee.
Cho often uses his childhood experiences as an Asian American in the South in his comedy. "I'm an Asian with a Southern accent," remarks Cho, "To a lot of people, that right there is funny." He frequently makes remarks about the church he goes to, however, not in a mocking way.
Cho appeared on many television shows in late-1980s and early-1990s including Bob Hope's Young Comedians Special, MTV's 1/2 Hour Comedy Hour and VH-1's Stand-Up Spotlight. His other TV credits include guest roles on various sitcoms such as Designing Women, Lenny, The New WKRP in Cincinnati and a starring role in the TV movie Revenge of the Nerds III: The Next Generation. In 1994, after he moved back to Tennessee, Cho got a call from NBC to host a revamped version of Friday Night Videos titled Friday Night. He commuted to L.A. weekly for two years. During this time, he also appeared on The Tonight Show with Jay Leno and The Arsenio Hall Show. Henry Cho recently earned his nickname, "Mr. Clean" for his always-clean comedy.
He has appeared in three feature films. First, starring opposite Tom Arnold and David Alan Grier in McHale's Navy. In 2001, he appeared in the Farrelly Brothers' movie Say It Isn't So with Heather Graham and Chris Klein. Most recently, in 2006, he appeared in Material Girls starring Hilary and Haylie Duff.
During the holiday seasons of 2003 and 2004, Cho toured around the U.S. with Amy Grant & Vince Gill, appearing live during the couple's show as a featured comedian on Grant and Gill's "Simply Christmas" tours.
In 2006, he had his own Comedy Central special entitled Henry Cho: What's That Clickin' Noise?.
In 2007, it was announced that he signed a deal with Touchstone Pictures and American Broadcasting Company to write, produce, and star in a television situation comedy series centered around Korean Americans living in the South. .