In the first quarter of Sunday night's high-stakes 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, one of the best players in the AFL, limped straight down to St Kilda's rooms and there will clearly be concerns over the severity of the injury.
The 23-year-old emerged a few minutes later but shuffled to the bench and took a seat in the back row, banging the glass behind him in frustration, before later having an ice bag strapped to his thigh.
St Kilda later confirmed Wanganeen-Milera would take no further part in the game, which was pivotal in the club's bid for a wildcard spot.
Veteran Mason Wood was ruled out with a calf injury late in the second quarter, which could finish his season too.
Ahead of the game, 10th-placed Carlton (40 points) were just one win clear of 11th-placed St Kilda (36).
Even a standard hamstring injury would realistically rule Wanganeen-Milera out of St Kilda's remaining games against Richmond and Gold Coast, seriously denting the Saints' hopes of a wildcard berth.
Wanganeen-Milera had been under an injury cloud all week, missing Thursday's training as he battled a hip pointer issue suffered in last week's loss to Sydney - but was ultimately cleared to play.
The 23-year-old has averaged 30 disposals, a goal and a direct goal assist this season, but has been red hot in recent weeks.
Two weeks ago, Wanganeen-Milera kicked four goals and had 46 disposals - one of three hauls of 40-plus touches in the past six weeks - while he still collected three goals and 24 possessions against the Swans last week.
The Saints had more injury scares before halftime.
Liam Ryan aggravated a left shoulder injury late in the first quarter but returned to the fray, as did former Blue Tom De Koning after heading down to the rooms with a second-quarter right shoulder issue.
Bradley Hill landed awkwardly from an aerial contest with Blake Acres and immediately grabbed just under his left knee.
Hill also headed to the rooms but returned.
Wood went down the tunnel soon after and was ruled out with a calf injury at halftime.
At the main break, Carlton - whose successful interim coach Josh Fraser is expected to throw his hat in the ring for the fulltime job this week - led a deflated St Kilda by 25 points.
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