I love comedy and I would write things to myself as an exercise in writing. I didn't do well for years, and I quit. I started to break down why I was afraid and started to look at people I admired, like Richard Pryor, Eddie Murphy, Freddie Prinze, George Carlin and all.

Lopez was a cast member and commentator for HBO’s hit sports show Inside the NFL for the 2003–2004 football season. Kirstie responded on Twitter "Don't worry about George's comments…just remember what happens to the big bad drunk woolf…falls in a boiling pot of vodka. He also claimed he had a physical altercation with Mencía over the alleged appropriation.

His stand-up comedy examines race and ethnic relations including Mexican American culture. He is mostly known for starring in his self-produced ABC sitcom George Lopez. He was the host of the late-night talk show Lopez Tonight on TBS until its cancellation on August 12 2011.