Danny Welbeck will miss England's Euro 2016 campaign and is unlikely to play again this year after undergoing knee surgery.
The Arsenal striker is set to be out of action for the next nine months, his club announced.
Welbeck suffered his devastating injury blow in Sunday's 2-2 draw against Manchester City.
He wrote on Twitter on Wednesday, adding a flexed bicep emoji: "I will be back stronger!"
Arsenal said on their website: "Danny Welbeck h as had surgery to his right knee. Specialists determined surgery was required after scans and tests revealed significant cartilage damage.
"Danny will miss the Euro 2016 Championship in the summer and his full recovery is expected to take approximately nine months."
The news is cruel setback for the 25-year-old, who only returned in mid-February from a 10-month lay-off due to an injury to his other knee. Welbeck scored five times after returning for the Gunners.
Welbeck's former club, Manchester United, sent a Twitter message that read: "Wishing you all the best in your recovery, Danny."
The development is terrible timing for England as the forward would probably have played a key role in Roy Hodgson's side at Euro 2016, having scored six goals in qualification.
The Three Lions boss planned to name his 23-man squad on Thursday, but pushed the announcement back to Monday in order to assess his players' fitness after the final round of Premier League fixtures.
Welbeck joins his Arsenal and England team-mate Alex Oxlade-Chamberlain on the sidelines, while questions remain over fellow Gunner Jack Wilshere who has only made two substitute appearances this term.
Everton defender Phil Jagielka has been out with a hamstring injury in recent weeks and Liverpool's Jordan Henderson has just returned to outdoor training after a knee ligament injury sustained last month.
Arsenal midfielder Wilshere sent his commiserations to Welbeck, writing on Twitter: "Devastated for my friend @DannyWelbeck but you've proved before you can come back a better player! Stay strong mate".
Another fellow England international and Gunner, Theo Walcott, added: "So gutted for you on your injury - You will come back stronger and all of us are thinking of you".
Arsenal centre-back Laurent Koscielny wrote: "Get well soon my friend @DannyWelbeck you are a strong man".
England still have plenty of attacking options for the tournament in France, with Wayne Rooney, Harry Kane, Jamie Vardy and Daniel Sturridge in the frame to travel as part of Hodgson's squad.