In February 2010, Slipper made his Super Rugby debut against the New South Wales Waratahs at Suncorp Stadium in Brisbane.

Slipper was named in the squad for the Australia A national rugby union team’s two matches against England in June 2010.

On 12 June 2010, Slipper made his debut for the Australia national rugby union team against England at Perth. He is the 843rd player in history to represent Australia. He quickly became a regular for the national team, playing in all six of Australia’s matches in the 2010 Tri Nations Series. Slipper featured in 13 of the Wallabies 14 Tests during 2010.

On 16 January 2015, Slipper was appointed the new captain of the Queensland Reds, replacing James Horwill, who would be leaving the Reds at the end of the Super Rugby season to join English Premiership side Harlequin F.C..

On 5 September 2015, he captained the Wallabies to a 47–10 victory over the United States at Soldier Field in Chicago, as part of their preparations for the 2015 Rugby World Cup.

In 2018, Slipper received a two-month ban after testing positive for cocaine.

In 2019, the ACT Super Rugby team, the Brumbies, added James Slipper to their team. He was a very positive addition to a successful season, with the Brumbies finishing on the top of the Australian conference. Slipper was said to add wisdom and depth to the team.