For Nigeria, anything but victory at the newly built Akwa Ibom International Stadium on Wednesday could be fatal for their chances of making the tournament in Equatorial Guinea.
They currently sit in second place in Group A, level on seven points with Claude Le Roy's Congo who face bottom of the group Sudan in their final qualifier.
Nigeria edge Congo in the pair's head-to-head results so need to match or beat their result against Sudan to ensure qualification.
Coach Stephen Keshi, who was recently re-appointed to the Nigeria hot seat, has asked his countrymen to pray for the team to do well.
"As regards the last qualifying match against South Africa, Nigerians should pray for us," Keshi said.
"They should pray for the players and they should be patient and they should come out en masse to support their team to win the match.
"They should pray for the boys to be in good health and that they should respond well in the match."
South Africa have already qualified for the AFCON but will want to end a 10-year wait for victory over Nigeria.
Shakhes Mashaba's men booked their place in Equatorial Guinea after a nervy 2-1 win over Sudan in Durban on Saturday.
Even though they are now guaranteed top spot in Group A, coach Mashaba has warned his players will not suffer from a loss of focus.
"I would like to say congratulations to the players, [but] we are still left with one game, against Nigeria," he said.
"I know people will think it is going to be a walkover; no, we are going to put out our best team. It is more than three points at stake when we go to Nigeria.
"It's going to be another tough game like the one we played today, which many thought was going to be easy. Thanks to all the supporters, their presence helped us conquer."
It is a decade since South Africa last beat the Super Eagles - a 2-1 friendly international victory in Johannesburg.
And newly appointed Bafana Bafana captain Dean Furman echoed his coach's sentiments by promising his team will head to Abuja to claim maximum points.
"The next match is against Nigeria and we want to maintain our undefeated record by getting a win," Furman said.