Mexico, who dominated the first half but faded in the second, struck back late through Rafael Marquez after 79 minutes when Bafana Bafana's offside trap went disastrously wrong.
South Africa hit the post just before the whistle.
The credible debut – from a team even many South Africans had written off until a sudden boost in form in recent months – came as Nelson Mandela's was absent from the occasion.
His great-granddaughter, Zenani, died in a car crash on the way home from a pre-World Cup concert, forcing the beloved 91-year-old father of post-apartheid South Africa to cancel his attendance and go into mourning.
Zenani, 13, was one of the nine great-grandchildren of Mandela, whose charisma and prestige is credited with helping South Africa win the World Cup bid in 2004.
Hundreds of thousands of South Africans crammed bars, homes and special fan parks for Friday's match in a show of national joy likely to accelerate unity in a nation still riven by race and wealth divides 16 years after apartheid ended.
"The rainbow nation has gathered together," teacher Disebo, 36, said among fans in the city of Bloemfontein.
Ear-splitting vuvuzela trumpets blasted and flags flew across the nation, with most public gatherings passing off peacefully.
|Mexico fans give some visual respite from the South Africa vuvuzela trumpet [AFP]
Three people were hurt in a crush at a fan park viewing of the opening match in Johannesburg.
Organisers, though, were thrilled with the first day.
"It is just fantastic that the first goal of Africa's first World Cup went to South Africa, we really couldn't have written a better script," local World Cup chief Danny Jordaan said.
Against Uruguay, France looked a far cry from the imperious team that won the World Cup on home turf in 1998.
Ahead of Saturday's match against England, the United States had an amusing reminder of their exotic surroundings when an elephant blocked the team bus – for the second time.
South Africa, who had begun to find some rhythym in the later stages of the first half, came out for the second having got over their stage-fright and there were no arguments about them taking the lead with a powerful shot from Tshabalala.
Five minutes later Itumeleng Khune denied Dos Santos with a superb save at the other end before Mexico gained a share of the points with 11 minutes left, although Katlego Mphela almost won the game for South Africa when he hit the post at the end.