After leaving university, it was seven years before Hughes found work as a stand-up comedian and he did a variety of jobs including working at an abattoir, as a bricklayer's labourer and a shop assistant. 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". 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. He is a regular performer at the Melbourne International Comedy Festival. Some of his shows have been released on CD, and on DVD.
Television
Hughes co-hosted the ABC comedy talk show The Glass House along with Wil Anderson and Corinne Grant. However, it was axed in 2006 amid political controversy. He has had guest spots on television programsThe Fat, Rove Live, The Panel, Thank God You're Here, Talkin' 'Bout Your Generation, The Project, Studio 10, All Star Family Feud, Under Melbourne Tonight, Spicks & Specks, The Living Room, Celebrity Name Game and Have You Been Paying Attention?. 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 showRove in 2007, with a weekly "Hughesy Loses It" segment. 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. 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 is quoted as saying, "It's definitely a tough decision, as we have had so many unbelievable moments on the desk. You meet some of the biggest stars in the world and chat with them and have some wonderful times". Hughes later said in an interview in 2016 that he left The Project stating: "The news cycle rarely changes. Nothing changes in so long. To sit there and talk about the same things every night, it was too much." Hughes will begin a year-long round of stand-up engagements around Australia, in Adelaide in February 2014, where he and his family will be based for five weeks before moving onto other venues. 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 28 October 2015, it was confirmed Hughes will be the new host of Australia's Got Talent in 2016. In October 2017, it was announced that Hughes would be returning to Network Ten to host a new panel show, Hughesy, We Have a Problem. In 2019, it was announced that Hughes will be one of the guessers on The Masked Singer Australia.
Radio
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. Dave O'Neil later left the station to join Vega 91.5.
Early in his career, Hughes had a brief appearance in an episode of Neighbours in 1998 playing a farmer named Knuckles who punched the character of Harold Bishop in the face and became embroiled in a scandalous relationship with Toadie. Hughes has also appeared in Ed Kavalee's comedy films Scumbus, which aired on Ch-10 in 2012 and the yet-to-screen Border Protection Squad.
He married Holly Ife, a reporter with the Herald Sun, on 31 December 2006. They have three children together. He gave up drinking alcohol when he was 22 after deciding that it had become a bad influence in his life. Hughes is a keen supporter of the Carlton football team in the AFL and even asked the Dalai Lama to bless Carlton: after doing so, the Dalai Lama commented: "It probably won't do much, and it didn't."
Controversy
During the 2007 Logie Awards, which he co-hosted with Adam Hills and Fifi Box, Hughes referred to radio shock-jock Kyle Sandilands as a "massive dickhead" to applause and laughter from the audience. Later that year, when interviewed on Enough Rope with Andrew Denton, Sandilands said of Hughes, "I hate him – the next time I see him I'm going to punch him in the throat." Hughes retorted by releasing an official apology, which said in part that Hughes was "sincerely and deeply sorry that Kyle Sandilands is a massive dickhead" and that "massive dickheads have the same rights as normal people."