Kepu comes into the team for fellow tighthead prop Ben Alexander, who is being rested for the Ireland match, which also opens the door for NSW Waratahs front rower Paddy Ryan among the replacements.
Ryan made his Test debut for Australia against France in Paris last year and has been a continually improving player for the Waratahs since playing his first Super Rugby match against New Zealand's Chiefs in 2011.
Joining Ryan on the bench is experienced 44-times capped hooker Tatafu Polota-Nau, who is set to put an injury-hit season behind him by playing his first game of 2013 for the Wallabies.
Polota-Nau missed almost half the Super Rugby season along with the British & Irish Lions series after breaking his arm, while a hamstring injury during the Rugby Championship delayed his return until now.
Australia are chasing their first back-to-back victories of 2013 after scoring a convincing 50-20 victory in their second game of the tour against Italy in Turin last weekend.
If Ewen McKenzie's men are successful it would be Australia's first triumph in Dublin since the Wallabies beat Ireland 30-14 in 2005.
AUSTRALIA Team & Replacements (v Ireland, Aviva Stadium, 2013 GUINNESS Series/Lansdowne Cup, Saturday, November 16, kick-off 5.45pm):
15. Israel Folau (NSW Waratahs) 12
14. Adam Ashley-Cooper (NSW Waratahs) 89
13. Tevita Kuridrani (ACT Brumbies) 7
12. Matt Toomua (ACT Brumbies) 9
11. Nick Cummins (Western Force) 10
10. Quade Cooper (Queensland Reds) 47
9. Will Genia (Queensland Reds) 52
1. James Slipper (Queensland Reds) 46
2. Stephen Moore (ACT Brumbies) 88
3. Sekope Kepu (NSW Waratahs) 35
4. Rob Simmons (Queensland Reds) 34
5. James Horwill (Queensland Reds) 45
6. Scott Fardy (ACT Brumbies) 7
7. Michael Hooper (NSW Waratahs) 25
8. Ben Mowen (ACT Brumbies) 12 (capt)
16. Tatafu Polota-Nau (NSW Waratahs) 44
17. Benn Robinson (NSW Waratahs) 64
18. Paddy Ryan (NSW Waratahs) 1
19. Sitaleki Timani (NSW Waratahs) 15
20. Liam Gill (Queensland Reds) 14
21. Nic White (ACT Brumbies) 8
22. Christian Leali'ifano (ACT Brumbies) 10
23. Joe Tomane (ACT Brumbies) 6