Early in the first quarter of Sunday night's clash at Marvel Stadium, Wanganeen-Milera handballed to teammate Max Hall, attempted to burst away then grabbed at his hamstring as he tried to receive the ball back.
A dejected Wanganeen-Milera limped straight down to St Kilda's rooms and the deflated Saints lost 15.10 (106) to 8.14 (62) as Carlton tightened its grip on a wildcard berth and the head coach role became Josh Fraser's to lose.
Asked about his players dropping like flies, Lyon said: "Well, I've been through it before ... When it's Nas, it's an arrow through the heart in a sense.
"At half-time, he just gave me a bit of a hug, really. So he's a positive person, but hopefully it turns out not too significant.
When the 23-year-old re-emerged and shuffled to the bench, he banged the glass behind him in frustration, before later having an ice bag strapped to his thigh.
Even a standard hamstring injury would rule Wanganeen-Milera, who had been cleared to play after a right hip issue, out of remaining games against Richmond and Gold Coast.
"For sure, it's a challenge, yeah," Lyon said.
"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. He's not going to play in the home and away season."
Veteran Mason Wood was ruled out with a second-quarter calf injury.
The victory takes 10th-placed Carlton (44 points) to 10 wins from 12 matches under interim coach Fraser, eight points clear of the chasing pack of St Kilda, GWS and North Melbourne (all 36).
Fraser is expected to throw his hat into the ring for the fulltime role this week, ahead of clashes with the Western Bulldogs (48 points) and leaders Fremantle, and appears an almost unbackable favourite.
When asked if he'd apply, Fraser said: "You're gonna get another straight bat.
"My preference tonight is to not make it about me if possible. And the reason I say that is it's a terrific night for our footy club.
"Our AFLW girls got a win tonight and you see the work that they put in consistently. On field it was another step forward for our playing group.
"... I think a lot of the credit around tonight's performance should be shared."
Carlton fans chanted "we want Fraser" late in the match.
"If I'm brutally honest I'm not comfortable with it, purely because I feel like I'm a product of a lot of people around me - but I appreciate it," Fraser said.
"I appreciate that they feel connected to us as a club at the moment. That's a really important thing for us moving forward."
Liam Ryan (left shoulder), former Blue Tom De Koning (right shoulder) and Bradley Hill (left knee) went down to the rooms but returned to play.
Carlton led by 25 points at halftime and 35 at three-quarter time.
Harry McKay kicked three majors to lead six multiple goal kickers.
Francis Evans (21 disposals, nine score involvements) was superb, Patrick Cripps (26 disposals), George Hewett (26) and Sam Walsh (26) got the grunt work done and Adam Cerra and Ollie Florent provided class.
Hall (30 disposals, 10 clearances, two goals) and Hill (31 disposals) were the most influential Saints, while Mitch Owens kicked 2.2 and Jack Higgins finished with 1.4.
