The 29-year-old Champion de Crespigny, who played for Castres Olympique in France in recent seasons, slots into the back row next to captain and number eight Harry Wilson and Fraser McReight.
The omission of back row enforcer Valetini and hulking lock Skelton, both of whom missed the Fiji test after suffering calf strains, is a big blow for Joe Schmidt's team.
Jeremy Williams and Nick Frost will be the starting locks, while Matt Faessler will start at hooker replacing Dave Porecki, who suffered a head knock against Fiji.
Scrumhalf Jake Gordon also missed the Fiji match with a hamstring problem but returns in a halves combination with Tom Lynagh, son of Wallabies great Michael.
Lynagh takes the place of Noah Lolesio, who suffered a neck injury against Fiji and was ruled out of the series.
James O'Connor's hopes of another Lions test, 12 years on from playing flyhalf in all three tests of the 2013 series, have been dashed for the moment, with flyhalf Ben Donaldson taking a spot on the bench.
Scrumhalf Tate McDermott was named as Gordon's back-up in the reserves, while outside back Andrew Kellaway makes a surprise return on the bench after missing the Fiji test.
"The whole squad has worked hard as a group to prepare for what’s going to be a massive challenge against an in-form Lions team," Schmidt said in a media release on Thursday.
"With the short runway leading up to such a big test match, we know we must adapt fast and improve quickly, from the performance we had against Fiji recently.
"We’re very much aware of the occasion and conscious of earning the support from the public through the effort they see on the field."
Wallabies XV vs British & Irish Lions:
15. Tom Wright, 14. Max Jorgensen, 13. Joseph-Aukuso Suaalii, 12. Len Ikitau, 11. Harry Potter, 10. Tom Lynagh, 9. Jake Gordon
8. Harry Wilson (captain), 7. Fraser McReight, 6. Nick Champion de Crespigny, 5. Jeremy Williams, 4. Nick Frost, 3. Allan Alaalatoa, 2. Matt Faessler, 1. James Slipper
Replacements: 16. Billy Pollard, 17. Angus Bell, 18. Tom Robertson, 19. Tom Hooper, 20. Carlo Tizzano, 21. Tate McDermott, 22. Ben Donaldson, 23. Andrew Kellaway