Zouma was substituted in the second-half during their 3-2 win against his former club Chelsea last weekend.
Scans have revealed the extent of his hamstring injury and the centre-back - who has impressed since arriving at the London Stadium in the summer - is now expected to be out of action for around 12 weeks.
Zouma has formed a formidable partnership with Angelo Ogbonna, but he has also been ruled out with a knee injury, with the double blow dampening West Ham's top-four hopes.
Frenchman Zouma has been a stalwart in defence both domestically and in Europe under David Moyes' stewardship this season.
The 27-year-old also grabbed the Irons' third goal in their 3-2 victory over Liverpool in November - a win that made rival clubs and fans take West Ham seriously as top-four contenders this season.
Queens Park Rangers' striker Charlie Austin has hailed Zouma's impact at West Ham, telling talkSPORT he is stunned neither Arsenal or Tottenham moved to secure his signature in the summer.
"Kurt Zouma is definitely up there," said Austin when asked about the season's bests signings.
"Mate, other clubs are looking at him and thinking, 'We should have went for him.'
"Spurs, Arsenal."
West Ham are keen to keep their top-four hunt alive, and reports claim they are busy searching for back-up ahead of the January transfer window.
According to The Sun, the Hammers are hoping to sign City centre-back Ake on loan when the market reopens.
The Dutchman has fallen down the pecking order at Man City since joining the club from Bournemouth last summer.
He has made just 22 appearances in 18 months at the Etihad, scoring two goals, including only five games in the Premier League this season, and a loan move would present an opportunity for him to rekindle his best form.