Ghana will welcome South Africa on 14 November at the Accra Sports Stadium in their quest to play at the 2021 African Cup of nations.
Ghana will face South Africa, Sudan and Sao Tome and Principe in the race for a ticket to the 2021 Africa Cup of Nations in Cameroon.
The top two teams at the end of the series will join 21 other nations and hosts Cameroon for the final tournament.
Ghana and South Africa played as part of preparations for this year's Afcon, the game ended 0-0 in the United Arab Emirates.
Their last encounter in a qualifying campaign was for the 2006 Fifa World Cup where the Black Stars emerged top of the group, recording back-to-back wins over Bafana Bafana in the process.