Ghana will face South Africa, Sudan and one of Mauritius or Sao Tome and Principe in the race for a ticket to the 2021 Africa Cup of Nations in Cameroon.
The development comes in the wake of the tournament's qualifying draw conducted in Egypt on Thursday.
The Black Stars, who suffered a Round of 16 exit at this year's championship, will have to battle it out with South Africa's Bafana Bafana and the Falcons of Jediane of Sudan in the second and final qualifying round which commences in November.
Earlier in October, Mauritius and Sao Tome will have a showdown in the preliminary round.
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 met only last month as part of preparations for this year's Afcon, the game ending 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.
Ghana's last meeting with Sudan came in the 2014 Fifa World Cup qualifiers where the Black Stars registered a 3-1 win away, having picked a 4-0 triumph in the first leg at home.
The Black Stars have only twice faced Mauritius, clinching a 7-1 victory in the first leg of the 2017 Afcon qualifiers and registering a 2-0 win in the return fixture away.
A meeting between Ghana and Sao Tome will be a historic first-ever encounter between the two sides.
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