Following early TV appearances on Theatre Sports (1987) and The Big Gig (1989), in early 1993 Micallef was offered a job writing for the Jimeoin show which was soon followed by an offer to also write for the sketch comedy show Full Frontal where six months later he took on the role as co-producer with Gary McCaffrie. In 1994, Micallef became a full time cast member of Full Frontal, where he became well-known for characters such as Milo Kerrigan, Nobby Doldrums and a send-up of Italian male model Fabio. Micallef recalls that the show was a good introduction to television comedy because, with an ensemble cast, its success did not hinge on his performance and he had more freedom to make and learn from mistakes. However, he was frustrated with the lack of control he had over his work in the series as well as the repetition of characters and gags.

Micallef's role on Full Frontal led to a 1996 special Shaun Micallef's World Around Him and three seasons of the two-time Logie Award-winning ABC series The Micallef Program (1998–2001), which he co-wrote and produced with long-time writing partner Gary McCaffrie. Since the series' end he has created and starred in two short-lived television series—the sitcom Welcher & Welcher (2003) and the variety show Micallef Tonight (2003)—and devised a series of telemovies, BlackJack (2003–present).

He has also had acting roles on the television series SeaChange (2000) and Through My Eyes (2004), and supporting roles in the films Bad Eggs (2003), The Honourable Wally Norman (2003), The Extra (2005), Aquamarine (2006), and The King (2007). In 2006, Micallef was a recurring guest on the Network Ten improvisational comedy show Thank God You're Here.

In 2007, along with partners McCaffrie and Michael Ward, Micallef developed the satirical comedy program Newstopia, which he hosted. The show began airing 10 October 2007 on SBS, and in August 2008 it was announced that a third series had been commissioned. In 2009, Micallef joined the Ten Network and is now hosting Talkin' 'bout Your Generation, which has been a hit on Australian television screens.