The giant lock pulled up late in Thursday's training session with a tight calf and was sent for scans ahead of the high-stakes match with Fiji in Saint-Etienne on Sunday (Monday AEST).
Wallabies coach Eddie Jones said Skelton would be given until kick-off to recover given the importance of the game, with Australia almost guaranteed a quarter-final berth with a victory.
"He got a bit of a knock at the end of training and he is just getting some extra medical work," Jones said.
Australia have already lost spearhead prop Taniela Tupou to a hamstring injury and first-choice halfback and vice-captain Tate McDermott after a head knock.
Jones wouldn't speculate on who would take over the captaincy, saying Skelton was at this stage still in the team.
Test centurion prop James Slipper will front up for his fourth Rugby World Cup among three changes locked in for the Wallabies starting team.
Slipper will replace injured Tupou in the starting front-row, becoming the third Australian to play in four tournaments alongside George Gregan and Adam Ashley-Cooper.
Lining up for his 132nd Test appearance, the 34-year-old missed the Wallabies' tournament-opening victory over Georgia in Paris with a foot issue, with Jones saying having Slipper play was "like having a coach on the field".
Veteran Nic White will replace McDermott in the No.9 jersey with rookie Issak Fines-Leleiwasa set to make his World Cup debut from the bench.
Jones has also brought athletic lock Nick Frost into the starting line-up ahead of Richie Arnold, who has been relegated to the bench.
Goal-kicking ace Ben Donaldson has been retained at fullback, with Andrew Kellaway again missing the match-day 23 at Stade Geoffroy-Guichard.
Jones said it was a difficult decision to leave out Kellaway, who was first pick at 15 leading into the tournament.
"Kells (Kellaway) has been training well but Donno (Donaldson) played very well at fullback in the last game, kicked well, and we feel like we've got the necessary cover there," the veteran coach said.
With Fiji losing their opening pool match against Wales, Australia can join the Welsh as the two teams to move through to the play-offs, with Jones underlining the importance of Sunday's clash.
"Fiji is the most important match of our Rugby World Cup campaign," Jones said.
"As we know they've got a brilliant ability to play counter-attacking rugby. They've got pace and they've got precision. That puts a different test to you.
"They're a team of power, they've got pace and they showed that in the last 10 minutes against Wales."
Jones has retained the remainder of the starting squad that downed Georgia 35-20.
Melbourne's Jordan Uelese has recovered from injury to line up for his 19th Test. He replaces Matt Faessler on a raw bench, with just Uelese and Rob Leota having more than seven appearances for Australia.
WALLABIES LINE-UP TO FACE FIJI
Angus Bell, David Porecki, James Slipper, Nick Frost, Will Skelton (c), Tom Hooper, Fraser McReight, Rob Valetini, Nic White, Carter Gordon, Marika Koroibete, Samu Kerevi, Jordan Petaia, Mark Nawaqanitawase, Ben Donaldson. Res: Jordan Uelese, Blake Schoupp, Zane Nonggorr, Richie Arnold, Rob Leota, Issak Fines-Leleiwasa, Lalakai Foketi, Suliasi Vunivalu.
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