A brace from striker Diego Forlan, including a late penalty that resulted in the dismissal of South Africa keeper Itumeleng Khune, gave Uruguay a comfortable 2-0 lead to ensure they would claim all three points.
South Africa’s 30-year-old stand-in keeper Moeneeb Josephs misjudged a cross to leave Alvaro Pereira with an easy tap in for Uruguay's third goal deep in stoppage time.
Uruguay, who aim to go beyond the group stage for the first time since 1990, lie on top of Group A with four points after holding France to a goalless draw in their first game.
South Africa, who surrendered a one-goal lead to share spoils with Mexico in a 1-1 draw in the tournament's opener last Friday, have one point from two games.
They will face a stiff test against France in their last game on June 22. A win that seems unlikely could keep their hopes of booking a last 16-berth alive.
Total Control
Uruguay took total control from the very beginning, helped by the presence of three natural strikers in Forlan, Edinson Cavani and Luis Suarez.
Suarez in particular caused the hosts' defense all sorts of problems with his neat stopovers and penetrating runs.
Uruguay deservedly grabbed the lead after 24 minutes when Forlan's powerful drive took deflection off the back of South Africa defender Aaron Mokoena and found the roof of the net.
He converted a penalty with ten minutes remaining to put the result beyond doubt after Khune tripped Suarez in the area when the latter looked certain to score.
Television replays suggested that Suarez might have been in an offside position in the build up.
Uruguay's second goal prompted many of the home fans to leave the stadium in agony while the vuvuzela trumpeters chose to remain silent for a while.
Pereira completed the rout five minutes into the additional time with a simple header to condemn South Africa to an embarrassing defeat.
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