The selection reunites a combination which last appeared on the brief tour which bookended the 2011 season, where the pair started against both the Barbarians at Twickenham and then Wales in Cardiff, with both matches being won.
Injury has hindered both players since, with O'Connor being ruled out of all of last year's internationals, firstly due to a lacerated liver and then by a hamstring complaint.
Genia featured until the midpoint of the inaugural Rugby Championship, signing off as the third captain employed by Australia during an extraordinary year when he damaged knee ligaments during the record fifth consecutive success over South Africa.
The half-backs reflect personnel changes of a magnitude that just six of the starting line-up from Australia's most recent outing - the 14-12 win over a Warren Gatland-prepared Wales in Cardiff at the end of 2012 - will feature from the kick-off this weekend.
The six players are full-back Berrick Barnes, centre Adam Ashley-Cooper, number 8 Wycliff Palu, lock Kane Douglas and props Ben Alexander and Benn Robinson.
Brumbies captain Ben Mowen will become the 869th player to represent Australia. The blindside flanker and lineout leader has led the Brumbies with distinction for the last two seasons, steering them to the top of the Australian conference in this year's Super Rugby standings.
Mowen's provincial team-mate Leali'ifano makes a belated debut for the Wallabies, a year later than expected - he cruelly breaking his ankle weeks before last June's Test series against Wales.
A Queensland State of Origin and Australian Kangaroo representative in rugby league, Folau joined the Waratahs this season after two years in Australian Rules football with Greater Western Sydney.
Folau has featured at full-back in Super Rugby but moves to the wing for his Test debut, with the 34-times capped Digby Ioane having recovered from a recent knee operation in time to gain the other wing berth
Up front, Douglas has won the race to partner returning skipper James Horwill in the second row, with Horwill's second row partner at the Reds, Rob Simmons, providing back-up from the bench.
The youngest member of the Wallabies squad - the 21-year-old Liam Gill - has also made the bench where he will act as understudy for Michael Hooper. Openside flanker Hooper featured on 13 occasions during a remarkable first season as a Wallaby.
Australia's starting front row features a combined total of 180 previous Test appearances, with Stephen Moore (76) the most-capped Wallaby hooker, while just one prop has featured in more Tests than the 56 played by Benn Robinson.
The trio is completed by Ben Alexander, whose 49th appearance will place him on the verge of becoming just the fourth Australian prop to complete a half century of Tests.
15. Berrick Barnes (NSW Waratahs)
14. Israel Folau (NSW Waratahs)
13. Adam Ashley-Cooper (NSW Waratahs)
12. Christian Leali'ifano (ACT Brumbies)
11. Digby Ioane (Queensland Reds)
10. James O'Connor (Melbourne Rebels)
9. Will Genia (Queensland Reds)
1. Benn Robinson (NSW Waratahs)
2. Stephen Moore (ACT Brumbies)
3. Ben Alexander (ACT Brumbies)
4. Kane Douglas (NSW Waratahs)
5. James Horwill (Queensland Reds) (capt)
6. Ben Mowen (ACT Brumbies)
7. Michael Hooper (NSW Waratahs)
8. Wycliff Palu (NSW Waratahs)
16. Saia Fainga'a (Queensland Reds)
17. James Slipper (Queensland Reds)
18. Sekope Kepu (NSW Waratahs)
19. Rob Simmons (Queensland Reds)
20. Liam Gill (Queensland Reds)
21. Nick Phipps (Melbourne Rebels)
22. Pat McCabe (ACT Brumbies)
22. Kurtley Beale (Melbourne Rebels)