Italian Destiny Udogie (21) and Spaniard Pedro Porro (24) are ruled out for the home clash with mid-table Wolves as the injuries that have blighted Spurs' season return.
"Destiny picked up a knock last week, jarred his knee, and he's not available for tomorrow. Don't think it's anything too serious," manager Ange Postecoglou told reporters on Friday.
"Pedro strained something in training, probably a couple of weeks for him. Hopefully he doesn't miss too many."
Tottenham head into Saturday's game in fourth spot, one point ahead of fifth-placed Aston Villa.
While the absence of Udogie and Porro, who have been outstanding this season, is a blow, Postecoglou said his side are used to dealing with injuries to key players.
"It doesn't change the way we play but I think I've said in the past a player brings their own sort of unique ability to each position," he said.
"The structure won't change and the way we set up won't change but different players bring different attributes.
"Pedro and Destiny have been outstanding for us this year. They're both improving but as I said they're missing now and there will be an opportunity for a couple of other guys to come in and make sure we maintain the levels we've set so far."
Despite a run of injuries and suspensions that derailed Tottenham's season after their best-ever start to a Premier League campaign, they are still very much in the mix to qualify for the Champions League.
Postecoglou has not set targets for his team but knows a strong finish to the campaign should ensure a top-four spot.
"We started the season strongly, obviously. We had some challenges through another period which we handled not too bad. The results weren't great but our competitive level was decent during that time," he said.
"You can have specific targets but ultimately if you can finish the season strong, you'll be in a good position."
Forward Son Heung-Min (31) is likely to start for Spurs after coming off the bench last week having returned from the Asian Cup, while his South Korea teammate Hwang Hee-Chan (28) will be available for 11th-placed Wolves having recovered from a knock.
