Following a cruciate knee injury in 2004, Byrne made his senior debut as a replacement against New Zealand in 2005. He was a regular starter during the 2006 RBS Six Nations and toured Argentina in the summer, scoring his first try in the second Test against Argentina in the 2006 summer tour.

Byrne had a successful 2006–2007 season with the Ospreys, scoring eleven tries over the course of the season for the Magners League title-winners. He received a Wales squad call-up for the 2006 Invesco Perpetual Series; Byrne appeared against the Pacific Islands and scored a try in the 38-20 victory.

He appeared once in the 2007 RBS Six Nations after recovering from a knee injury, in Wales's defeat to eventual champions France and received a call-up for Wales's two-Test tour to Australia in May 2007, making the starting XV in the loss of the first Test in Sydney. Byrne was named in Gareth Jenkins's 41-man preliminary Rugby World Cup 2007 summer training squad in June but failed to make the final cut.

In November 2007 Byrne was selected in Wales Caretaker Coach Nigel Davies's 31 man squad ahead of the Prince William Cup clash with South Africa. He made the starting line-up but had to withdraw from the team due to an injury picked up whilst on Regional duty with the Ospreys.

In January 2008 Byrne was included in Warren Gatland's 28 man squad for the 2008 RBS Six Nations, and played in every game of the Grand Slam winnig campaign. The fullback enjoyed a hugely successful season, winning many plaudits for his superb form and scoring three tries to boot; one against England in the victory at Twickenham and a brace against Italy in his man of the match performance.