The Slovakia international was ruled out for up to two months on Monday after sustaining a broken metatarsal in his right foot against Unirea Urziceni last week.
Lee acknowledges Liverpool's defensive ranks have fallen victim to bad luck this season, however the assistant manager believes the Reds have enough quality to handle the latest setback.
"I think when you lose someone of his quality, it's always a blow, particularly in that position," Lee told Liverpoolfc.tv.
"It's a massive disappointment because Martin's been instrumental in us gaining some momentum. We've kept a lot of clean sheets, which is very important.
"It is a blow to the club because it limits our options. But we don't bemoan that - we accept it because it's part and parcel of the game.
"We've had a bit of bad luck in that position throughout the season, but that's football and we'll have to adapt to life without him for a period of time.
"It's disappointing and frustrating, but we have to get on with life without these players."
Skrtel's defensive colleague Daniel Agger picked up a knee injury during Sunday's 2-1 win over Blackburn and underwent a scan on Tuesday.
"We don't know the full extent of it," said Lee. "We've got a bit of time thankfully because we don't play until Monday, so we will see what happens in the next two to three days. Hopefully it won't be as bad as we first thought."
Fabio Aurelio was forced to leave the field during the first half against Rovers after suffering a strain in his quadriceps, and Lee admits he shares the Brazilian's disappointment after an injury-hit campaign.
He added: "It appears to be a bit of a thigh strain. It's disappointing for him because he has been dogged with injuries throughout the season.
"But again, we will work on him, give him good medical attention and try to get him back playing as soon as possible."
Meanwhile, Lee spoke of his delight at the news Steven Gerrard will captain England in tonight's international friendly with Egypt at Wembley.
"It's great for Steven, his family, the football club and everyone concerned," the Anfield No.2 said.
"Everyone knows what Stevie Gerrard is about. It'll be a great night for him and let's hope he has a lot more."
With a host of other senior Liverpool stars on international duty this evening, Lee concedes he will be nervously awaiting news on whether the Reds' players have come through their matches unscathed.
He said: "I think I'd be lying if I didn't say that. Obviously you want them to remain fit.
"It's a contact sport and you don't know what's happening when they're away all over the world, you just hope they come back with not too many knocks."