Early in the first quarter of Sunday night's clash with Carlton at Marvel Stadium, Wanganeen-Milera clutched his left hamstring as he attempted to burst forward to receive a handball.
The dejected star, 23, limped straight down to St Kilda's rooms and later returned with ice on his hamstring before the deflated Saints lost 15.10 (106) to 8.14 (62).
It left St Kilda eight points outside the wildcard places with only games against Richmond and Gold Coast left.
Lyon described the Wanganeen-Milera injury as "like an arrow through the heart" and hoped it wouldn't be "too significant", with the Saints unsure of its severity.
"I'm not sure what the worst case is, but I would think, what I saw - and I don't know much about hamstrings - like, your minimum three weeks," Lyon said.
"He's not going to play in the home and away season."
The Saints will hope scans confirm Wanganeen-Milera's hamstring isn't the degree of severity that would potentially eat into his pre-season.
Lyon said the Saints were "scratching our heads a little bit on the soft tissue" injury given St Kilda had an eight-day break.
The hamstring was the opposite side to the hip pointer concern Wanganeen-Milera had been dealing with.
But Lyon noted Wanganeen-Milera had missed some training sessions in recent weeks, which was "not ideal" given he was normally a player who always trained.
The Saints are already without Max King (hamstring), Jack Sinclair (calf) and Sam Flanders (Achilles)
"Oh, we haven't used it as an excuse to now, and I don't really want to, to be honest," Lyon said.
"You've just got to build out a list capable of handling those sort of injuries."
Jack Silvagni and Liam Ryan are managing shoulder issues and Lyon was unsure whether the Saints would rest them, while flagging he could turn to some hungry VFL players.
"There was a really good VFL performance, so we'll really look heavily at that," he said.
"We've got to set some standards and not accept - as coaches and players - not accept some stuff, so we'll look to bring some in."
Lyon believed 11th-placed St Kilda - who recruited hard over the off-season - had been very competitive and their percentage of 101.6 showed it, while acknowledging some might feel they hadn't improved this season.
"But that's OK, I've gotta wear it, I'm fine, I'm a big boy, I'm happy to take what comes," he added.
"But my job - leaders shepherd, protect and nurture and challenge their people under pressure, and that's my job and I'll continue to do it until I'm either tapped or I tap myself."
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