Dominic Solanke is not in Tottenham's squad to face Everton this afternoon with his injury now confirmed.
It has forced Spurs to start captain Heung-min Son up front as their injury crisis continues to get worse.
Solanke has largely led the line on his own due to the club's fitness issues but has now suffered a knee problem himself.
Brennan Johnson is also absent along with Timo Werner, while Yves Bissouma is unfit and Ben Davies, who is starting this afternoon, won't last the full 90 minutes, according to Ange Postecoglou.
Postecoglou confirmed the news ahead of kick-off at Goodison Park, saying: "Brennan and Biss picked up knocks against Arsenal.
"Biss not too bad, Brennan probably a little bit more significant.
"Dominic tweaked his knee yesterday in training trying to take a shot and misses today and not sure of the extent of it."
Postecoglou continued: "It's always a blow when you lose key players for any club.
"Obviously in the situation we're in that's further exemplified by the fact that we don't really have the depth to cover it at the moment, but that's okay.
"We've got 11 fit players and that's what you need to start a game."
Solanke is one of multiple players to miss the visit to Merseyside and there are concerns that a lengthy spell on the sidelines awaits.
He also sat out the reverse meeting with Everton after picking up a knock on his Premier League debut for Tottenham.
The England international sat out the 4-0 win over the Toffees in August as well as the 2-1 defeat to Newcastle in the club's next match.
However, since his return, Solanke has been near-ever present for Tottenham in the Premier League, scoring seven times.
Aside from sitting out a 1-1 draw with Fulham in December due to illness, the 27-year-old has started every other top-flight match.
Postecoglou's lack of cover in forward areas following Richarlison's injury woes have also meant Solanke hasn't been afforded a rest.
The latter has played the third-most amount of minutes in the Premier League for Tottenham this season, only behind Pedro Porro and Dejan Kulusevski.
Solanke has also racked up over 500 minutes across three cup competitions, with 11 goals in total since arriving from Bournemouth.
He was even needed to cameo from the bench in the FA Cup third-round 3-0 extra-time win over National League Tamworth.
Only this week, Postecoglou all-but foreshadowed Solanke's injury by sharing his fear that his No.9 was being overloaded.
The Australian manager admitted he was in the process of targeting a new forward this month to relieve the burden on Solanke.
Postecoglou said: "If we can get him some help, yeah [he will continue to fill the gap left by Harry Kane].
"Dom has just been outstanding in the way he’s carried the frontline for us during this period.
"With the way we play, we put a lot of demands on that position. It’s not just him standing up there scoring goals, it’s working hard for the team.
"I really think if Richy was available, I think [Dom] would have been able to contribute even greater for us in terms of his output in goals.
"I really love what he brings to us as a team from a football perspective, from a cultural perspective.
"The only growth we’ve seen in recent times is him and Deki [Dejan Kulusevski] becoming on-field leaders in the team.
"With Dom being a new player, it probably would have been easier for him to slip in and do his job but he’s taken on the responsibility of helping the whole team. He’s been great for us.
"I really feel there is more to him and his game. We’ll be able to get more out of him if we can him some help."
Postecoglou will now be sweating on a prolonged absence for Solanke ahead of a crucial spell in Tottenham's faltering season.
The 2-1 defeat to rivals Arsenal in the north London derby confined Spurs to 15th in the table - already 14 points off the top four.
The Lilywhites haven't won a Premier League match since beating bottom-of-the-table Southampton on December 15.
That is their only victory in their past nine top-flight encounters, with Everton having the chance to move within four points of Tottenham with a game-in-hand.
Solanke faces a race to be fit for the Carabao Cup semi-final second-leg clash against Liverpool at Anfield.
He provided the assist for Lucas Bergvall's winner in the first meeting between the two, with Spurs holding a slender 1-0 advantage.