Sithole found himself at the centre of a disastrous afternoon as Bafana suffered a 2-0 defeat at the Estadio Azteca, leaving Hugo Broos' side under immediate pressure in Group A.
The 26-year-old midfielder was involved in the opening goal after receiving a risky pass from captain Ronwen Williams deep inside South Africa's half. Mexico forward Julian Quinones capitalised on the mistake and slotted the ball through Williams' legs in the ninth minute to hand the hosts an early lead.
Things deteriorated further for Sithole shortly after halftime when he received a straight red card for bringing down Brian Gutiérrez as the last defender following another defensive breakdown.
Mexico took full advantage of their numerical superiority and sealed victory in the 67th minute through experienced striker Raul Jimenez.
South Africa's frustrations boiled over late in the game when Themba Zwane was also sent off after an altercation with Gilberto Mora, marking the veteran midfielder's first red card in national team colours.
Despite Sithole's difficult performance, McKenzie urged supporters not to single out the midfielder.
"This is not tennis; this is football. We win as a team or lose as a team. Don't blame yourself, Yaya. This wasn't your best performance, but you took one for the team with that red card. We appreciate all our players. Come back stronger, son," McKenzie wrote on X.
With Sithole and Zwane suspended, Broos will now be forced into changes ahead of Thursday's must-win encounter against the Czech Republic.