The match is expected to be played in front of a record 1.5-billion people, with the eyes of the world truly on the famous stadium that is so steeped in football history.
There are any number of factors that could decide the game, but we pick five that could be crucial to the final result.
Handling the moment
Who can settle quicker and who will feel the nerves will be crucial. Certainly, the pressure is on Mexico; no-one outside of South Africa likely thinks Bafana Bafana have much hope.
But with that expectation, felt in the stands and by the 1.5 billion watching from around the world, comes a weight that will be felt more and more by the Mexican side the longer the game goes on at 0-0.
An early goal for them will really settle them down and could lead to a handsome victory as it would force Bafana Bafana out of their defensive set-up.
If South Africa get the first goal, that will create panic within the home team and play into Bafana’s hands as they look to catch their hosts on the break.
This will be the biggest game of their careers for both sets of players. Who will buckle under that weight?
A defensive game-plan
South Africa coach Hugo Broos has a set-up for tournament football, especially in matches where he feels South Africa are outgunned.
It is about staying compact, frustrating the opposition and hitting them on the break with the pace his side possesses up front and their ability to get the ball up the pitch quickly.
It is not rocket science, but was hugely effective for the team on their way to the bronze medal at the 2023 Africa Cup of Nations.
This is a step up in quality from the teams they faced there, bar perhaps a very handy Nigeria side who they held to a draw in the semi-finals before losing on penalties.
But it only works while the match is level. If Bafana are forced to come out of their shell, they can be brutally exposed.
Aerial fallibility
Bafana have shown in recent times that high balls into their box have been difficult to deal with.
It is why Broos has brought the tall Ime Okon and Olwethu Makhanya into the squad at such a late stage, to try and undo what has become a bad habit.
Mbekezeli Mbokazi is an excellent defender and incredibly strong in the tackle and quick across the ground. But he is 1.77m tall (5ft 10in).
The average height of centre-backs at the 2026 World Cup is around 1.87m, a full 10 centimetres taller than Mbokazi. Both Okon and Makhanya are in this ballpark.
That is why Mbokazi needs a tall centre-back alongside him to try and negate his relative shortness, but this is an area opposition teams can target.
Mexico at home
Mexico have not lost a home competitive fixture since a shock 2-1 loss to Honduras in World Cup qualifying in 2013. Two goals in three second-half minutes turned things around for the visitors after they fell behind.
Bafana need to hope for some such scenario, where the Mexican veil slips for a period in the game and they can take advantage. One goal leads to two and so on.
But Mexico are supremely confident on their own patch and will be roared on by their fanatical fans.
To win, Bafana would need to do something no-one has managed in 13 years. It is also why a draw would be an excellent result.
Hosts undercooked?
Mexico’s last 14 games have all been friendly internationals (W6 D6 L2); they have not played a competitive fixture since winning the CONCACAF Gold Cup in July last year.
That is almost 12 months, and there is a school of thought that says this lack of competitive edge could hurt them.
In that time, Bafana Bafana have finished a tough World Cup qualifying campaign and been to the 2025 Africa Cup of Nations.
Is there a school of thought that they might be more battle-hardened than their hosts?
It may be a small consideration, but in World Cups, every tiny percentage of advantage can help.
