The decision is a massive blow for the Black Stars as they face a tough clash with South Africa in Johannesburg before taking on Sao Tome and Principe during the international break.
Ghana coach Charles Akonnor was keen on unleashing his best players for the two matches later this month but the decision of Palace means he has to look for other options.
The English Premier League has taken into consideration the current epidemic trends in the world before deciding not to release the two Black Stars players.
The current COVID-19 restrictions in England are preventing the Eagles from letting the two players join the Black Stars camp for the doubleheader.
Ayew and Schlupp will require a 14-day mandatory quarantine on their return from the international assignments.
This will keep the duo out of up to four Palace fixtures and thus making the London-based club do block them from joining their teammates for the two games.
The Black Stars take on South Africa on 25 March 2021 at the FNB Stadium before they host Sao Tome and Principe three days later in Ghana.
Ghana and South Africa lead the standings with 9 points with a goal difference separating them.
Sudan is 3rd on the table having 6 points whilst Sao Tome languishes bottom with no single victory.