Wallabies tryscorer Lalakai Foketi is returning to Australia with a suspected leg fracture, with coach Dave Rennie planning to make wholesale changes for the next Test against Italy.
The Australians fell to a heartbreaking 30-29 defeat to Six Nations champions France in Paris in the second match of their five-Test European tour, with the home side securing the win with a 75th minute try.
Midfield ace Foketi finished off one of the tries of the year in the 18th minute to give his team a first-half lead.
In a brilliant team effort the Wallabies moved the ball through the backline over 95 metres before Foketi skipped away from the defence to score.
However, the Waratahs centre limped off six minutes later with what was described as a shin injury, replaced by Hunter Paisami.
Rennie said post-match the injury was believed to be "significant", and his worst fears were confirmed by scans.
The Wallabies announced on Monday that Foketi would immediately fly home to Australia. They are yet to name his replacement, leaving Paisami and Len Ikitau as the squad's only specialist centres.
The tourists had some positive news, however, with prop Allan Alaalatoa (concussion) and fullback Tom Banks (ankle) set to be available against Italy.
Having opened the tour with a win over Scotland before the France loss, the Australians will face Italy in Florence on Sunday (AEDT).
They haven't played the Italians since a 26-7 victory in 2018.
With Tests looming against world No.1 Ireland and Wales, Rennie said he would look to "freshen up" the squad.
"We'll definitely make changes next week," Rennie said.
"I've talked about sharing the load as playing five Tests against Six Nations sides in consecutive weeks is pretty demanding, so we want to utilise the squad and give guys opportunities to impress."
As part of his halfback rotation plan Jake Gordon is set to start, with Tate McDermott the back-up No.9.
France-based lock Will Skelton, who made a notable impact off the bench in the second half against France, is set for his first start since 2016.
"He'll probably get a start next week," Rennie said of the La Rochelle giant.
"It was good to get him off the bench. I thought he had a really big impact as we'd expected and I look forward to getting more minutes out of him next week."
The Italians overpowered Samoa last weekend, scoring six tries en route to a 49-17 scoreline.
Rennie said his team selection would reflect their respect for Italy.
"We're not going to do anything that doesn't respect Italy. They had an excellent win and we're well aware of their ability," he said.
"We're also looking big picture. We're going to Ireland the following week and Wales the week after that, and we need to utilise the whole squad."