In December 2001, Hughes joined comedians Kate Langbroek and Dave O'Neil to co-host a weekday breakfast program Hughesy, Kate & Dave from 6am to 9am on Melbourne's Nova 100.
In the past, he has worked for the Triple M network of Australian active rock radio stations.
Appearing onstage he acknowledges that he was "just horrible" but after three attempts over six months he gained his confidence and went on to become a headline act. In the AFL season he is a part of the Network Ten Saturday night show Before The Game alongside Mick Molloy, Lehmo, Andy Maher and Neroli Meadows.
Hughes worked on Australian television show Rove in 2007, with a weekly "Hughesy Loses It" segment.
In December 2013, Hughes resigned from his full-time position on The Project to return to stand-up comedy.
Hughes will, however, appear once a week on the show from wherever he is around the country.
Hughes later said in an interview in 2016 that he left The Project stating "The news cycle rarely changes. To sit there and talk about the same things every night, it was too much." In October 2014, Hughes guest-starred in an episode of ABC-TV's Julia Zemiro's Home Delivery, in which Zemiro accompanied Hughes back to his home-town of Warrnambool to reminisce about his childhood and to explore what influenced him to embark on a career in comedy.
On January 2018, Hughes began hosting Hughesy, We Have a Problem on Network Ten.
After dreaming about being a comedian since he was a youngster, his first comedy gig came at age 22 when he was living in Perth doing labouring jobs and he decided, "I'm going to have a crack".
In 2008–09, the segment evolved into a recurring segment known as "Help me Hughesy," where he would rant about a given topic.
On 20 July 2009, Hughes began co-hosting the half-hour Channel 10 show The 7PM Project, which later expanded to become the hour-long The Project.
His regular co-hosts were Charlie Pickering, and Carrie Bickmore.
In June 2011, Hughes was one of the few people to be granted a one-on-one interview with the Dalai Lama during his visit to Australia.