Jamie Vardy and Jonny Evans face months on the sidelines, with Leicester boss Brendan Rodgers down to just nine outfield players.
Striker Vardy has been ruled out until March with a hamstring problem while defender Evans has had surgery on his own hamstring injury.
It leaves Rodgers down to the bare bones ahead of Saturday’s FA Cup third-round visit of Watford.
Vardy suffered a hamstring injury in the 1-0 win against Liverpool in December and it was initially hoped he would only be out for a month.
Rodgers said: “Jamie will be out for a number of weeks. It’s been unfortunate for him but we’re looking at up to eight weeks. He’ll be out for a period of time.
“His is the higher end of his hamstring, you are looking into March for Jamie. He doesn’t need an operation, that was the only good news from it.”
Evans has been plagued by a foot issue for almost a year but it is the hamstring injury which he suffered against Newcastle last month which will keep the Northern Ireland international out.
Leicester are now looking at bringing in cover on loan, with Jannik Vestergaard their only available senior centre-back.
Rodgers added: “Jonny has had an operation so he will be April. With his hamstring he needed that.
“(Bringing in a replacement) is certainly something we need to look at. The players who have been filling in are away at the African Nations and it doesn’t give us a lot of cover.
“It’s something the club are working very hard on to see what we can do. There’s not an endless pot of money but we have to look at that and see what we can bring in. We are working hard behind the scenes.”
The hosts will also be without the injured Patson Daka, Ryan Bertrand, Ricardo Pereira, James Justin, Wesley Fofana and Caglar Soyuncu.
Boubakary Soumare, Luke Thomas and Filip Benkovic are also out, with Kiernan Dewsbury-Hall struggling with a calf problem and Timothy Castagne a doubt.
Kelechi Iheanacho, Daniel Amartey and Nampalys Mendy are on duty at the Africa Cup of Nations.
The Foxes host Watford after lifting the FA Cup for the first time in their history by beating Chelsea 1-0 last May.
Youri Tielemans’ second-half strike won the trophy for the Foxes, with Rodgers eager to defend their title.
“It was such a memorable competition for us, it was amazing and against such illustrious opponents,” he said.
“The memory will be with us for a lifetime, it will connect us all, but now it’s the beginning of it again. It’s about winning it.
“We go into the game with a very strong mindset to win the competition again.”