In 2009, the Irish Independent described Ó Briain as "Terry Wogan's heir apparent as Britain's 'favourite Irishman'".

Ó Briain was born in 1972 in Bray, County Wicklow,[7] and adopted into what he described as "a stable home" where he enjoyed a happy childhood with his "supportive" parents.

'"[9] Ó Briain spent three years as a presenter on the bilingual (Irish and English) children's programme Echo Island but came to prominence as a team captain on the topical panel show Don't Feed the Gondolas (1998–2000) hosted by Seán Moncrieff.

[14] Ó Briain's stand up international career took off around this time as he began to tour heavily, performing across Europe, Asia, Australia and North America, with gigs in Dubai, Paris, Adelaide, Shanghai and New York City.

Around this time, Ó Briain presented the weekend game show It's a Family Affair on RTÉ Television.

[16][17] In 2011, Ó Briain took part in two shows of the 16-date Uncaged Monkeys tour with Professor Brian Cox, Robin Ince, Ben Goldacre, Simon Singh and Chris Addison.

He had originally planned to perform the show on debut tours to the United States and Canada in 2020, but this was postponed after the first four US dates, in early March, due to the COVID-19 pandemic.

[19] Due to the ongoing COVID-19 pandemic, a portion of the tour in Ireland that was originally planned for January 2022 was pushed back to March through June 2022.

The most regular panellists have been Colin Murphy, Ed Byrne, Neil Delamere, Andrew Maxwell and Mairéad Farrell.

Around 2002, with his profile rising in the UK due to his one-man shows at the Edinburgh Festival Fringe, Ó Briain began making appearances on UK television shows such as Bring Me the Head of Light Entertainment (a Channel 5 production) and Never Mind the Buzzcocks.

On 14 September 2005, Ó Briain appeared as a guest on Room 101, where he got rid of children's television presenters (following his work as a presenter on Echo Island) and once-in-a-lifetime experiences (he was given a once-in-a-lifetime experience on the show by being the second guest to pull the lever that opens the chute to Room 101 – the first had been former host Nick Hancock).

[25] Since 2006, Ó Briain has starred in the BBC's Three Men in a Boat series, with Griff Rhys Jones and Rory McGrath.

Ó Briain has also been an extensive newspaper columnist, with pieces published in many national papers in both the UK and Ireland, from The Sunday Times to The Daily Telegraph.

[26] In a review of Tickling the English, Ó Briain was described as Sir Terry Wogan's heir apparent as Britain's "favourite Irishman".

[28] Ó Briain has hosted the British Academy Video Games Awards 9 times between 2009 and 2019, including 2012, when highlights were also shown on Challenge.

From 3 to 5 January 2011, Ó Briain and Brian Cox presented Stargazing Live on BBC Two, three programmes based at the Jodrell Bank Observatory, scheduled to coincide with the conjunction of Jupiter and Uranus, a partial solar eclipse, and the Quadrantid meteor shower.

[31] The two presenters hosted a second series of three-hour-long programmes, plus follow-up 30-minute shows called Stargazing Live: Back to Earth, from 16 to 18 January 2012.

From 16 April 2012, Ó Briain presented an eight-episode series of School of Hard Sums with co-host Marcus du Sautoy on Dave.

Each episode was themed and Ó Briain along with a guest attempted to solve various conundrums posted by du Sautoy.

[33] In 2013, Ó Briain joined Jack Dee, Chelsee Healey, Greg James, Melanie C and Philips Idowu in Through Hell and High Water, a Comic Relief challenge which involved British celebrities canoeing the most difficult rapids of the Zambezi River.

From January to March 2016, Ó Briain presented Tomorrow's Food, a three-episode series alongside Angela Hartnett, Chris Bavin and Dr Shini Somara.

[36] Ó Briain presented the 2016 reboot of Robot Wars starting on 24 July, as well as the subsequent two series in 2017.

He hosted a revival of the classic quiz show Blockbusters, which began airing on Comedy Central on 21 March 2019 until 5 December 2019.

[39] On 23 June 2022, Ó Briain was confirmed to star as a contestant in series 14 of C4 comedy game show Taskmaster.

[42] Ó Briain had a cameo role as a generalised alternative comedian in the 2013 British film The Look of Love directed by Michael Winterbottom.

I'm technically Catholic, it's the box you have to tick on the census form: 'Don't believe in God, but I do still hate Rangers.

[citation needed] In early 2010, a series of small demonstrations were held outside some of Ó Briain's tour venues, urging him to publicly denounce the sport of greyhound racing due to the dog's death.