The 26-year-old left the pitch with a groin injury during Saturday's 2-2 Premier League draw with Wolves, and the club have now confirmed that after being assessed by medical staff, he will play no part in the game.
NU spokesman: "Newcastle United can confirm that Papiss Cisse has been withdrawn from the Senegal squad to face South Africa on Wednesday.
"The striker, signed in January from Freiburg, sustained a slight groin injury in Saturday's 2-2 draw against Wolves and was substituted midway through the second half of the match.
"Having been assessed by United's medical staff, Cisse will not take part in Senegal's friendly."