Lukhan Salakaia-Loto, Adam Coleman and Marika Koroibete are the only three players to retain their starting spots from the side thrashed 36-0 by the All Blacks three weeks ago.
Flanker David Pocock will captain the Wallabies on his return from injury, with regular skipper Michael Hooper among those to miss the game as coach Michael Cheika takes a safety-first approach before Japan.
Seven players in Australia's Rugby World Cup squad have Samoan heritage, with hooker Jordan Uelese named to make his first start for the Wallabies and flanker Salakaia-Loto and second five Matt Toomua also named in the run-on team this weekend.
Prop Scott Sio is also likely to feature off the bench however hopes of a showdown in front row between brothers Allan and Michael Alaalatoa have been dashed, with the former not included in the match-day 23.
Matt To'omua said it will be an extra special occasion for the Samoan players in the Wallabies team.
"I think we've got about five or six Samoan guys who come from Samoan heritage in the squad so I'm sure my dad will be torn, he'll probably be wearing half and half a little bit," joked the Melbourne Rebels utility back.
"So, if I get a chance to play against the Manu dad will be very excited - I'll have a lot of family in both camps I think."
Australia have won four of their five previous tests against Samoa however the Manu prevailed 32-23 when the teams last played in a similar fixture prior to the 2011 Rugby World Cup.
1. James Slipper, 2. Jordan Uelese, 3. Sekope Kepu, 4. Rob Simmons, 5. Adam Coleman, 6. Lukhan Salakaia-Loto, 7. David Pocock, 8. Jack Dempsey, 9. Will Genia,
10. Bernard Foley, 11. Marika Koroibete, 12. Matt To'omua, 13. Adam Ashley-Cooper, 14. Dane Haylett-Petty, 15. Tom Banks.
Reserves: 16. Tatafu Polota-Nau, 17. Scott Sio, 18. Taniela Tupou, 19. Luke Jones, 20. Liam Wright, 21. Rob Valetini, 22. Nick Phipps, 23. James O'Connor.