Manyisa, who dropped to the bench despite scoring against Senegal, has now been ruled out of the match with a knee injury.
The midfielder, who has been playing out of position on the left-hand side of midfield, sustained a blow to the knee during training on Monday evening.
SAFA confirmed the news via it's official Twitter account on Tuesday, when it tweeted: "Manyisa withdrawn from tonight’s squad after failing to recover from a knee injury suffered at training last night"
Manyisa joins central defender, Thulani Hlatshwayo, on the injured list for the must-win fixture against Ghana's Black Stars.
South Africa coach Shakes Mashaba made four changes for tonight's match including the somewhat controversial decision to start the match with Kaizer Chiefs' goalkeeper Brilliant Khuzwayo after Darren Keet and Jackson Mabogkwane had featured in the previous two fixtures.
South Africa must beat Ghana to have any chance of progressing to the last 8 of AFCON 2015.
Bafana Bafana starting XI:
Brilliant Khuzwayo (GK), Anele Ngcongca, Thabo Matlaba, Rivaldo Coetzee, Eric Mathoho, Dean Furman (C), Andile Jali, Mandla Masango, Thuso Phala, Tokelo Rantie, Bongani Ndulula.
Kick-off of both fixtures in Group C are set for 20:00.
Follow the match LIVE with Sport24's interactive match commentary!