The 63-year-old star's upcoming Prime Video special, which was filmed on 27 and 28 September at the Dolby Theatre in Hollywood, will be the last chance for fans to see him on stage as he's ready to call it a day.
Speaking on 'The Tamron Hall Show', he said: "It is the last one. I've subjected the American people to enough of my c***.
"It seems like the right time; it's been the one thing that has just never left me my whole life and it's a wonderful place to leave it at this particular point."
George is keen to spend more time with his daughter Mayan Lopez, who he co-created and stars with in NBC comedy series 'Lopez vs Lopez'.
He said: "I love the show."
George's decision comes months after he ended a stand-up show early, citing an "unruly crowd".
The 'Spy Next Door' star was criticised by Eagle Mountain Casino in California for having "let down his fans and sold out audience by walking out and ending his show 30 minutes early" back in June.
His representative hit back in a statement: "It's the venue or casino's job to provide a good experience for both the artist and the fans, but the casino failed in this regard.
"The audience was overserved and unruly, and the casino staff was unable to provide a safe and enjoyable experience for the artist and guests. George's personal security team worked with the venue security staff to maintain order, ensure safety, and eject disruptive individuals.
"Unfortunately, the casino security team was not adequate to accomplish this task. George is not obligated to perform in an unsafe environment. He feels badly that those who came to see the show were unable to do so as a result."
But the casino then disputed George's statement.
A spokesperson said: "Lopez's statement providing reason for exiting the show abruptly after not saying anything to casino management or security, came as a shock to everyone including casino management. The claims of unruly guests are not consistent with casino footage and surveillance.
"Casino security and Lopez security team worked together to make sure there was no filming with phones as requested by Lopez. It was the job of Lopez's private security team to inform casino security if they wanted to escort anyone out which never occurred. Under the casinos discretion no guests were unruly or providing an unsafe environment.
"Mr. Lopez or his private security had every opportunity to inform casino team if they wanted a guest escorted out and they did not. The two prior openers, also comedians, did not have any concerns or issues, so this was quite a shock to everyone attending."