Karl Robinson says Ahmed Kashi and Jay Dasilva could be sidelined for up to eight weeks.
Both players, who have been consistent performers this term, picked up injuries in the 2-0 defeat to Shrewsbury.
Kashi damaged his foot when he was running and Dasilva hurt his ankle. They will miss between four to eight weeks of action.
Charlton have been plagued by injuries to first-team stars since the opening day of the season.
Addicks boss Robinson told News Shopper: “We think it could be a lot longer [than four weeks for Kashi and Dasilva]. I think four weeks is being very, very optimistic. It’s four to eight weeks.
“My head has slowly gone with this now. I don't think there’s been a manager or any players who have had this much [bad] luck for a long time. I’ve had enough of it.
“With these new injuries, Jay Dasilva did his ankle when the pitch gave way, it’s no one’s fault. With Kashi, our physio who’s been around for a long time said it’s the first injury he’s ever seen in football. It’s a tendon in the bottom of the foot.
“We don't know how he did it, it was just as he was running. When you look at the injuries we’ve had, Stephy Mavididi’s one was nobody’s fault.
“Billy Clarke’s injury was a cruciate ligament and Leon Best’s injury was a cruciate ligament. You then look at Tariqe Fosu who was out for 14 weeks. Jason Pearce, 14 weeks and a bit longer. I’ve never known anything like this.”
Jay Dasilva | Picture: Benjamin Peters Photography
An injury crisis has affected Charlton in their last three campaigns.
But this season has presented worse problems as Robinson has never picked a team from a fully fit squad.
And the former MK Dons manager can’t put his finger on why these injuries keep on occurring to his players.
He said: “It’s certainly not the training, you know how religious I am in my attention to detail in training. So it’s not that.
“You're always going to get a large portion of injuries throughout the season. So I’d say 60 per cent is through fatigue, which everyone gets. But it’s the 40 per cent on top of that which is unexplainable. It’s silly things.
“The three hamstrings with Naby Sarr, Tariqe’s groin and Stephy, it’s a tendon issue. We’ve never seen a load like this.
“We've never seen anything like this in my time as a manager and coach in relation to these type of injuries.
“We always moan as managers when things don't go quite right. But with the long-term injuries we've had that are unexplainable, we’re almost sitting here scratching our heads on what we've done wrong.
“I feel sorry for the players and fans because I’m telling you now, I believe when this squad is fully fit, it is good enough. We've seen that when our players have been fit, we’re as good as anybody.”
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