The Matildas star limped out of the derby tie within just the first 20 minutes of City's 2-0 home defeat after requiring several minutes of treatment on the Joie Stadium pitch after she appeared to wrench her right knee while overstretching for the ball.
With anxiety clear on the City bench featuring players who have suffered serious ACL injuries in the past, interim manager Nick Cushing reported after the game: "It doesn't look great imminently.
"To lose Mary Fowler in an important game at an early stage, and to lose a goal, was catastrophic.
"It is her knee. I don't want to speculate, but we're not fearing the worst."
There had earlier been obvious concern from the City medics before the grimacing 22-year-old was able to get back to her feet and, briefly, it appeared as if she felt she might be able to get back into the action.
But she had to be substituted in the 24th minute by Naomi Layzell, and could then only watch on the bench as her dream of any English silverware this season died following their League Cup final defeat and Champions League exits at the hands of Chelsea.
Fowler was still being treated when the already injury-depleted City went 2-0 down to United in the 22nd minute, with Grace Clinton adding to the lead they'd been given by a brilliant strike from Celin Bizet after just six minutes.
It was a dispiriting end to what had been an another impressive week for Fowler when she netted for the Matildas back home in their win over South Korea before jetting back for City's big game.
For City, Fowler has been a key creative spark all season, especially while a series of injuries have been afflicting some of their other stars, like Khadija Shaw, Lauren Hemp and Vivianne Miedema.
City's defeat ended any prospect of Australia's two premier women's players going head-to-head in the Cup final at Wembley in May, with Sam Kerr's Chelsea having reached the final with a 2-1 win over Liverpool on Saturday.
Kerr herself faces a race against time to feature in the final as Chelsea have reported she's still "a few weeks away" from getting back into action after her own long-standing ACL injury.
Holders United, though, look set to offer a big challenge to the English champions Chelsea after reaching their third final in a row.
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