Byrne was a footballer and played for Home Farm and St. Kevins Boys in North Dublin. He became a professional player, and joined Leeds United as a goalkeeper in 1995, and was a squad member of the FA Youth Cup winning team of 1997. He played for Leeds for two years, leaving when his contract expired in June 1997. He played in a reserve game for Scarborough and in a trial game with Cambridge United, before returning to join Dublin club Shelbourne. He then signed for Cobh Ramblers playing 15 games in all competitions, then St. Francis F.C., all in Ireland’s League of Ireland.

In June 1998, Byrne attended an audition for new Irish boyband, where Boyzone manager Louis Walsh approached him to join his new venture, Westlife. Byrne joined Westlife along with Kian Egan, Mark Feehily, Shane Filan and Brian McFadden. Byrne revealed in Westlife: Our Story that he had wanted to change the name of the band to West High; but the others preferred Westlife. With Westlife, Byrne has had 25 top ten UK singles, 14 of which, were number one, 7 number one albums and has sold in excess of over 55 million records worldwide. It is certified that Westlife have sold 20.2 million records and videos in the UK across their 14-year career – 6.8 million singles, 11.9 million albums and 1.5 million videos. Byrne also had a number one single in Ireland in 2002, alongside the Republic of Ireland national football team and Dustin the Turkey with the Irish 2002 FIFA World Cup anthem, “Here Come The Good Times (Ireland)”. He also co-wrote many of Westlife’s songs.

Throughout the years, Byrne has appeared on Children in Need and Comic Relief several times. In 2001, he co-hosted Children in Need live from Belfast and in 2011 and co-hosted a BBC Radio 2 radio special with Patrick Kielty for the cause.

In 2002, Byrne guest-hosted an edition of CD:UK with Cat Deeley.

Byrne was born to parents Yvonne and Nicholas (d. 2009). He has an older sister, Gillian, and a younger brother, Adam. Byrne married his teenage sweetheart Georgina Ahern, whom he met when they were about 12 years old. The two were married on 5 August 2003 at the Wicklow Register Office, Wicklow, County Wicklow. Twin sons Rocco and Jay were born on 20 April 2007. The civil ceremony was followed by a church blessing on 9 August at the Roman Catholic Church of St Pierre et St Paul in Gallardon, Eure-et-Loir, France and a reception at the nearby 16th-century Château d’Esclimont. On 29 April 2013, Byrne announced on his Twitter page that he and his wife Georgina were expecting their third child, and on Irish television it was announced that the baby was due around Halloween. Daughter Gia was born on 23 October 2013.

On 14 May 2009, Byrne was a substitute for a Liverpool Legends XI that played against an All Star XI in a Hillsborough Memorial match to mark the 20th anniversary of the Hillsborough disaster. All the proceeds from the match went to the Marina Dalglish appeal. He represented the Republic of Ireland at U15, U16 and U18 levels. He is a fan of Celtic FC, and on 9 August 2011 played in a Celtic Legends XI at Celtic Park in front of a 54,000 crowd against a Manchester Utd Legends team. Byrne participated in and won Soccer Aid 2014. He scored in the match, played at Old Trafford. He was the only non-professional player to score in the match. The Rest of the World team won the game 4–2.

Byrne has narrated stage shows such as The Snowman Christmas Special and the Picture of You documentary dedicated to former Boyzone member Stephen Gately who died on 10 October 2009.

In addition, Byrne presented several editions of the Celebrity Sunday radio programme on RTÉ 2fm in 2010. Listeners tuned in from as far and wide as Mexico, Chile, the United Kingdom, Philippines and Indonesia. The fourth and final edition of the programme, broadcast on 14 February 2010, trended worldwide on Twitter. FM104 publicly offered him a job the day Westlife announced their split.

In 2010, Byrne and his family organised the ‘Nikki Byrne Twilight Ball’, a fundraising event, in memory of their father who died in November 2009. The event raised over €200,000 and completely funded a television and radio heart attack awareness campaign in connection with ‘The Irish Heart Foundation’. Byrne, and his wife Georgina, are keen supporters of the Irish Premature Babies charity. Byrne also supports UNICEF and has taken part in several UNICEF Campaigns, such as the UNICEF ‘Euro for Zero’ campaign where the goal was to raise as much money as possible in November 2010 for Child Survival Programmes.

In October 2012, Byrne hosted the RTÉ reality TV show Football’s Next Star. The series followed ten young hopefuls competing for a chance to win a place with Celtic Football Club’s youth squad.

In 2013 through 2015, 2017 and 2018 Byrne presented the Irish votes at the Eurovision Song Contest. He also co-hosted the short-lived TV talent show The Hit on RTÉ One along with Aidan Power.

On 4 February 2014, Byrne signed a contract with RTÉ 2fm to host a new weekday show from 11 am to 2 pm.

In January 2015, Byrne started hosting the new weekly National Lottery game show, The Million Euro Challenge on RTÉ 1, although the show was axed that July.

In early January 2016, it was rumored that RTÉ had internally chosen Byrne to represent Ireland in the Eurovision Song Contest 2016. Byrne had not yet confirmed or denied such information but announced that he would grab the opportunity with both hands if given. On 13 January, Byrne was confirmed to be the Irish singer for the 2016 contest in Stockholm with the song, “Sunlight”. He performed in the second semi final on 12 May 2016, but failed to advance to the final.

In January 2017, Byrne started hosting an Irish version of the TV show Dancing with the Stars, alongside Amanda Byram and with Jennifer Zamparelli from 2019.

In October 2018, a video was posted to Westlife’s official social media platforms announcing the group’s reunion as a four-piece. In 2019, the group will be headlining “The 20 Tour”, named in honour of Westlife’s 20th anniversary since its formation and the release of its first single, “Swear It Again”, in 1999. In addition to touring, Westlife will also be releasing new music. “Hello My Love”, the first single from the group’s upcoming album, will debut on the Graham Norton Show on 10 and 11 January 2019.

In March 2019, Byrne left 2FM to rejoin the newly reunited Westlife.

In June 2020 he hosted RTE does Comic Relief during the COVID-19 Pandmic