Luke's wife Mickayela is a cousin of fellow Kiwi rugby league international Sonny Bill Williams, with whom he also played in the juniors at the Bulldogs. Luke is a cousin of England international Rangi Chase.
Prior to making his professional debut, Luke played Jersey Flegg Cup for the Bulldogs alongside fellow New Zealander and future Kiwis teammate Sonny Bill Williams. Luke made his NRL debut for the South Sydney Rabbitohs in round 12 of the 2007 NRL season against the Melbourne Storm at Olympic Park Stadium, coming off the bench. In Round 19 Against the North Queensland Cowboys Issac Luke had his first NRL start, playing at hooker. He scored his first NRL try and was awarded the Brut Man of the Match award for his efforts. Luke tasted finals football in his debut year, coming off the bench in the Rabbitohs 30 – 6 loss to the Manly-Warringah Sea Eagles. He was awarded the John Sattler Rookie of the Year at the South Sydney annual Red and Green Ball and presentation night held at the AJC function centre at Randwick Racecourse Sydney. He also was second only to Israel Folau in the dally m rookie of the year award. His year was capped off by being named in the Train on Squad for the New Zealand Kiwis.
Luke started the season well but a broken bone in his hand in the round 3 loss to the Penrith Panthers sidelined him for 4 weeks. He came back in round 7 against the Brisbane Broncos and added some much needed spark to the team but they came up short going down 32 – 18. His return from injury came just in time for him to make his test debut for the Kiwis for the ANZAC day test at the SCG. He started the game at hooker and had a solid debut. Luke was named at Halfback For the Round 8 clash against the North Queensland Cowboys to accommodate both himself and fellow hooker George Ndaira in the starting side. During Round 13 against The Warriors, Luke was instrumental for Souths, which included setting up a great try to put Souths ahead at Half Time. He was named Man of the Match. Round 14 against the Titans Luke scored his first career double and slotted the match winning penalty for a 24–23 victory. In August 2008, Luke was named in the New Zealand training squad for the 2008 Rugby League World Cup, and in October 2008, he was named in the final 24-man Kiwi squad.
Luke was considered one of the 2008 Rugby League World Cup tournament's 'Players to Watch' by NRL Live. He was then a crucial part of the Kiwi side that lifted the World Cup in 2008, beating Australia 36 – 24 before over 50,000 spectators at Brisbane's Lang Park. Also in 2008, he was named in the Taranaki Rugby League Team of the Century.
Luke made 68 NRL appearances for Souths in the 2009, 2010 and 2011 seasons. In none of those seasons did the Rabbitohs qualify for the finals series. He represented New Zealand in the 2009, 2010 and 2011 Four Nations tournaments, playing off the substitutes bench for the Kiwis' win the 2010 edition. For the 2010 Anzac Test, Luke was selected to play for New Zealand at hooker in their loss against Australia. Luke's 2011 Four Nations tournament ended in controversy after he was criticised for a series of cynical tackles on opposing players. Luke admitted that in a match against England, he had attempted to break the leg of Rangi Chase, England's New Zealand-born half-back.