Holmes (23 disposals) shone and on-ball partner Bailey Smith (35) was outstanding in the Cats' 15.12 (102) to 11.9 (75) victory on Thursday night at GMHBA Stadium.
But Holmes was taken straight down the race in pain after his right leg twisted underneath him in the final quarter, and he reappeared on crutches with his ankle in a protective boot after the match.
"They won't know until they've had a decent look at it, but it was pretty clear that he couldn't come back on, so that's always my measure in the immediate aftermath," Scott said.
"There has been that (ankle syndesmosis) suggestion but I covered my ears, to be honest. I'll just wait to see what it is and deal with it when we know.
"Obviously it's frustrating, but it is the game. If you asked me a couple of weeks ago who do you really not want to lose, (Jeremy) Cameron and Holmes would be up there."
Shaun Mannagh (hamstring tightness) also failed to finish the match.
Geelong (10-8) ended a three-match losing streak and strengthened their grip on a finals spot, with Smith and James Worpel (24 disposals, seven clearances) important contributors.
Gryan Miers kicked three goals on return, Ollie Henry and Ollie Dempsey added two each, and Jhye Clark (25 disposals) was busy after being recalled.
Key forward Jay Polkinghorne tallied two goals and eight marks in an impressive debut, called up to take injured spearhead Cameron's spot in the team.
Cats tagger Oisin Mullin ensured a tough night for Nasiah Wanganeen-Milera, wearing the Saints superstar like a glove.
Wanganeen-Milera had 21 disposals - his lowest tally since round one - in his milestone 100th game.
The 23-year-old vented his frustration about the close attention to umpires and had a free kick overturned for pushing Jhye Clark into the ground.
"There's four umpires, they do their job. They've got a difficult job," Saints coach Ross Lyon said.
"It's all part of becoming a great team and a great player, right?"
St Kilda ruck Rowan Marshall fought manfully for 33 disposals, 12 clearances and two goals, as well as a club-record 26 contested possessions.
Mattaes Phillippou (28), Darcy Wilson (29) and Hugo Garcia (30) were all busy.
But it wasn't enough to end a long drought at Kardinia Park, where the Saints have now lost 14 consecutive games and last won in 1999.
Geelong kicked the opening four goals in a dominant start and fended off a St Kilda challenge in the third term.
The margin ballooned to as much as 47 points clear before the Saints kicked the last three goals of the match in junk time.
