Smashed in their past three outings against the Bulldogs, the Saints were forced to deal with adversity from the start on Sunday when Sinclair went down in the first quarter and De Koning in the second.
St Kilda battled on bravely and stayed in the contest until late but the Bulldogs' early buffer was enough as they secured a crucial win, 12.11 (83) to 8.13 (61).
St Kilda initially insisted Sinclair hurt his calf, but there are fears it could be a more serious Achilles injury after his foot was put in a moon boot when he hobbled from the field in pain.
An Achilles rupture would rule the Saints co-captain out for the rest of the season, while a calf injury would likely mean far less time on the sidelines.
"There's speculation about an Achilles," Saints coach Ross Lyon said.
"I'm not in a position to comment any further, except to say they think it's more calf.
"You can't live in that space (of complaining about injuries) because there's still opportunities to get it done.
"Sinclair helps all that efficiency ... but I thought our spirit was strong."
Highly-paid recruit De Koning produced a strong start but suffered a heavy hit to the ribs in the second quarter.
St Kilda's No.1 ruck was assessed in the rooms, before briefly returning to the field late in the second term.
But De Koning's condition worsened and he was ruled out of the match during the main break, later going to hospital for scans.
"Rowan should be fine, and TDK is precautionary," Lyon said.
The Saints' other ruck, Rowan Marshall, battled on after receiving treatment on a shoulder injury in the third quarter.
Star midfielder Nasiah Wanganeen-Milera was comfortably St Kilda's best, having 37 disposals to three-quarter-time and finishing with a career-best 44.
After a heavy loss to Adelaide last week, the Bulldogs responded in workmanlike fashion, with a clear focus on defence.
Against the Crows, the Bulldogs conceded nine first-quarter goals, but on Sunday they blunted St Kilda's attacking weapons while Buku Khamis and James O'Donnell held down the defensive 50.
Superstar captain Marcus Bontempelli (34 possessions and 13 clearances) was typically excellent and his classy goal late in the second quarter was the highlight of a scrappy contest.
His willingness to take ruck contests to help Tim English early in the match was surprising, especially given he has dealt with soreness for most of the season.
"There were some things we did differently ... we really took on some risks tonight with what we did, and we changed different things that sometimes worked, but sometimes didn't," Bulldogs coach Luke Beveridge said.
"It's just a great credit to our players to be willing to come in and out of their responsibilities.
"We need to do things differently to beat the teams in the back end of the year."
The win lifts the Bulldogs to seventh (9-6), with a trip to the SCG to face premiership contenders Sydney to come following their bye next week.
St Kilda (6-9) also have a week off before meeting last-placed Essendon in round 17 as they face an uphill battle to qualify for the wildcard weekend.
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