Jay Rodriguez faces six months on the sidelines after rupturing his anterior cruciate ligament, extinguishing the Southampton attacker's hopes of going to the World Cup.
The 24-year-old was in the running for a spot in England's 23-man squad, having enjoyed a fine season with Saints in which he netted 17 goals.
Such form saw Rodriguez handed his Three Lions debut in November's friendly against Chile, but his hopes of a spot on the plane to Brazil have been cruelly taken away.
The forward landed awkwardly during Saturday's 4-1 defeat at Manchester City and Southampton confirmed he has ruptured his anterior cruciate ligament.
"Southampton Football Club can confirm that, following his injury on Saturday against Manchester City, Jay Rodriguez has been diagnosed as having suffered a rupture to his anterior cruciate ligament," a statement on the club's official website, www.saintsfc.co.uk, said.
"This will keep him out of action for six months and regrettably means he will not be fit for selection by the English national team at this summer's FIFA World Cup in Brazil.
"The 24-year-old has already been scanned and has met with a specialist knee surgeon. He will be having a routine operation shortly.
"The club will post any further updates once Jay's rehabilitation is under way."
Southampton's statement confirmed what many had expected given the way his right knee buckled beneath him.
Rodriguez looked understandably tearful as he was taken off on a stretcher, receiving a standing ovation by both sets of fans at the Etihad Stadium.
Roy Hodgson witnessed the incident first hand. The England manager has now lost another player to an anterior cruciate ligament injury after Arsenal forward Theo Walcott earlier in the year.
Southampton director Les Reed said: "Jay is naturally disappointed, but is determined to get back playing for Saints as soon as possible.
"Everything will be done to return him to full fitness and deliver a speedy recovery.
"Jay has asked us to pass on his gratitude to everybody who has shown him their concern and sympathy during the 48-or-so hours since his injury.
"Everyone at the club now wishes Jay well and we will support him, along with his family, to ensure that an international career plays a big part in his future."