The selection reunites a combination which last appeared on the brief Spring Tour which bookended the 2011 season, where the pairing started against both the Barbarians at Twickenham and then Wales in Cardiff, with both matches being won.
Injury has hindered both since, with O'Connor being ruled out of all of last year's Test programme, firstly due to a lacerated liver, and then by a hamstring complaint. Genia featured until the mid-point of the 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 in Perth.
The inside back combination reflect personnel changes of a magnitude that just six of the starting XV from Australia's most recent outing - the 14-12 win over a Warren Gatland-prepared Wales at Cardiff at the end of 2012 - will feature in the run-on side for the Tom Richards Cup opener.
These players are fullback Berrick Barnes, centre Adam Ashley-Cooper, No 8 Wycliff Palu, lock Kane Douglas and the props, Ben Alexander and Benn Robinson.
The 27-year-old Barnes excelled from the back for Australia last year, where he was one of five fullbacks used by the Wallabies for the campaign, but featured from the position in six of the final eight Tests, missing the other two through injury. Barnes, who in Cardiff became just the 37th player to appear in 50 Tests for the Wallabies, was Australia's leading point-scorer in 2012, with the 110 he scored, boosting his career tally to 193.
O'Connor - 208 points from 37 Tests -, Barnes, Leali'ifano and replacement back Kurtley Beale - 80 points from 36 Tests - all provide specialist goal-kicking prowess within the match night squad.
The night will be a massive occasion for all of the Wallabies, but none more so than Brumbies skipper Mowen, who will become the 869th player to represent Australia.
He does so in the state where he was raised, in front of a huge contingent of family members.
Starting on the blindside flank, from where he will call the lineouts, Mowen 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. He had earlier appeared for both Queensland and New South Wales prior to heading to Canberra.
Provincial team-mate Leali'ifano makes a belated debut, a year later than expected, after he appeared certain to be Australia's outside half in the series against Wales this time last year, before cruelly breaking his ankle weeks out from the start of that tour.
The gifted 25-year-old has started exclusively from inside centre this term and claims that Test spot, with his experienced Brumbies team-mate Pat McCabe running from the bench as he completes a return after his Spring Tour came to a shuddering halt when he broke a bone in his neck.
Leali'ifano will become Wallaby number 868 in what will be the 549th Wallaby match to be sas a Test by the Australian Rugby Union while the selection of the 867th Wallaby will complete an incredible opening to the rugby union career of Israel Folau, who will join dual-international ranks less than halfway through in his first season in the game.
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 winger's berth
Up front, Douglas has won the race to partner the returning Wallabies skipper James Horwill in the second row, with Horwill's second row partner at the Reds, Rob Simmons, backing the pair from the subs bench. The youngest member of the Wallabies squad; 21-year-old Liam Gill, has also made the bench, where he will act as understudy for Michael Hooper, the team's Player of the Tour from last year's Spring trip to Europe.
Hooper featured on 13 occasions during his remarkable freshman season as a Wallaby while Gill's Test introduction was no less impressive, appearing in eight Tests.
The Australian 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.
Although the run-on line-up features three who are playing their first Tests, the starting XV is still an experienced one, boasting a combined 519 previous Test appearances.
Qantas Wallabies (v British & Irish Lions)
15. Berrick Barnes (NSW Waratahs)
14. Israel Folau (NSW Waratahs)
13. Adam Ashley-Cooper (NSW Waratahs)
12. Christian Leali'ifano (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 (Brumbies)
3. Ben Alexander (Brumbies)
4. Kane Douglas (NSW Waratahs)
5. James Horwill (Queensland Reds, captain)
6. Ben Mowen (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 (Brumbies)
23. Kurtley Beale (Melbourne Rebels)
Referee: Chris Pollock (New Zealand)
Assistant Referees: Craig Joubert (South Africa), Romain Poite (France)