In the morning of January 26, 2003, on the day of the Super Bowl, Milonakis, after he decided not to attend a friend's Super Bowl party, recorded a video titled "The Super Bowl is gay". He posted the video to the website AngryNakedPat.com which within two weeks became a viral video. A writer for ABC's new late-night show, Jimmy Kimmel Live!, spotted it and got Milonakis on the program. Milonakis first started rapping on YouTube; his first song was called "The Andy Milonakis Rap". He was in Three Loco, a group of the rap artists Dirt Nasty and Riff Raff but on September 26, 2014 he announced that the group had broken up. He currently has his own cooking show on MUNCHIES, a YouTube channel that is part of the VICE network. In December 2016, he announced he was joining the Baited podcast, with YouTubers Anything4views and Keemstar. According to Twitchmetrics on February 26, 2017 he is currently the fastest growing streamer in the IRL category of the popular streaming website Twitch.
In a 2005 interview, Milonakis said he would use comedy as a means to cope with incessant bullying: "Humor is a great defense mechanism. If you're a serious, fat, young-looking kid, you're not going to be the most popular guy in high school."
Milonakis has growth hormone deficiency, which makes him look and sound like an adolescent boy despite the fact that he is a fully adult man.