Enner Valencia suffered "significant" injuries to his right knee and ankle in Thursday's Europa League game, West Ham revealed on Friday.
The forward is set to see a specialist on Monday to determine the full extent of the damage.
"It is too early to put a timescale on how long Enner's recovery and rehabilitation period may be," West Ham said in a statement.
West Ham already face a difficult trip to Romania on Aug. 6 to stay in the Europa League after Thursday's 2-2 draw at home against FC Astra, and that task will be made even harder without Valencia.
The 25-year-old Ecuador forward fell following a first-half challenge and left the game, his first since returning from duty with Ecuador at the Copa America.
West Ham coach Slaven Bilic expressed concern after the game.
"I am worried to be fair," Bilic said. "And this is the reason I am unhappy tonight. I am not happy with the result of course but this is not as important as the injury.
"It looks serious but we won't know for sure until he has a scan."
The news will come as a blow to the Hammers, who are already without club-record signing Andy Carroll for the start of the new season.
Valencia enjoyed an impressive start to his career at Upton Park after joining last summer but his goal on Thursday was only his third in front of West Ham's home support.
Diafra Sakho, a reported target of Manchester United, also arrived 12 months ago but he was suspended for the meeting with Astra, although thankfully for Bilic the Senegal international can play the return leg in Romania next week.
Another option in attack is Mauro Zarate -- with the diminutive Argentinian looking for a fresh start at the club.
He scored a tremendous solo goal on Thursday and looks more at home than he did under previous boss Sam Allardyce, who allowed him to leave on an ultimately unsuccessful loan move to QPR.
Despite the hosts going 2-0 up they had to settle for a draw after conceding twice following the 59th-minute sending off of defender James Collins. However, midfielder Mark Noble insists the players will not be disheartened by Astra's comeback.
"We were disappointed by the result," he told West Ham TV. "But if you ask if we are angry and upset I would say no because we have got to try and win on Thursday night and then we have got Arsenal on Sunday.
"With the quality that we had on the pitch it could have been a lot more but they had a wonder strike and a freak goal and it made it hard for us.
"We can't be upset because if we go into the Premier League feeling sorry for ourselves we are going to get punished. We have got to stay positive and I am sure we will be fine."
Information from Press Association was used in this report.
