Morocco beat Guinea Bissau 3-0 in Casablanca to open up a five-point lead in Group I and will secure top place if they beat Guinea in Rabat on Tuesday.
Only the group winner from each of Africa's 10 groups advances to March's playoffs, where the five African representatives for Qatar 2022 will be decided.
A horror blunder from Ethiopia goalkeeper Fasil Gebremichael saw him let Tebogo Mokoena's free kick slip through his hands and gift South Africa the half-time lead.
Although the home side were level soon after the break, South Africa scored twice in the final 20 minutes through Mothobi Mvala and Evidence Makgopa to move to seven points.
Ghana, with Milovan Rajevac returning as coach, were back at full strength for their game against Zimbabwe at Cape Coast and romped to a 3-1 triumph with goals from Mohammed Kudus, Thomas Partey and captain Andre Ayew.
Morocco have a 100% record after three games with Guinea Bissau second on four points and Guinea on three. Guinea were held to a 2-2 draw by Sudan earlier on Saturday and must beat Morocco on Tuesday to stop the north Africans from winning the group.
Senegal and Namibia were both wasteful but still managed to conjure up five goals in their entertaining clash in Dakar, with Mane among those guilty of squandering gift-wrapped chances.
They are eight more African qualifiers on Sunday and more games to come on Monday and Tuesday.