The Maritzburg United player injured his knee in during a club training session on Monday and will thus not be available for the competition which kicks off on June 21.
“Brian (Mandela) got injured in training. He is one of our key players and will not be available for Afcon. We will need to find a solution,” coach Sébastien Migné told reporters from Kenya's training camp in France.
“It is not good for us and for him as well. Musa Mohamed also picked up a knock (in Harambee Stars’ friendly match against Madagascar). We cannot take a risk with him against DR Congo but he could be available for Afcon.”
He, however, expressed optimism that he has enough depth to fill the void.
“We won against Ghana without key players. It is always problematic for the coach but we will try to find a solution,” Migne added.
Kenya will be meeting The Lions of Teranga for the fourth time at an Afcon group stage, as they did in 1990, 1992 and in 2004.
All of Kenya's matches will be staged at the 30 June Stadium in the capital of Egypt, Cairo.