A brace of goals from Diego Forlan helped Uruguay ruin South Africa's World Cup party in Pretoria to virtually secure Oscar Tabarez's side a place in the knockout stages.
Former Manchester United striker Forlan struck with a wonderful drive on 24 minutes to break the deadlock with his first goal of the tournament, but one of the best so far.
His dipping effort took a slight deflection to leave Bafana Bafana goalkeeper Itumeleng Khune helpless on a miserable night for the hosts.
Forlan made it 2-0 from the penalty spot with 10 minutes remaining after Khune tripped Luis Suarez with a clumsy challenge to earn himself a straight red card and leave the home side with no way back.
Just to rub further salt into South Africa's wounds Alvaro Pereira added a third deep into stoppage time to complete what was an emphatic victory for the South Americans.
Despite backing from fanatical fans and the incentive of knowing a victory would see themselves put one foot in the last 16, Carlos Alberto Parreira's side never looked in contention.
The defeat, South Africa's first in Pretoria and first since Parreira returned for his second spell in charge, now leaves their dreams of making progress from Group A in danger of turning into a nightmare.
But the win was no more than Uruguay deserved after they dominated the contest from start to finish.
Oscar Tabarez's men showed more attacking flair and ambition from the start, with Forlan right at the heart of it all.
The home defence had no answer to his pace, passing and vision and the outcome seemed inevitable once he had put them ahead with a stunning strike, his first goal of the tournament.
His second arrived courtesy of Khune's clumsy challenge and when he made no mistake from the spot the game was over as a contest.
But Uruguay were not finished and continued to press hard, so it came as no surprise when Pereira made it 3-0 from point blank range with virtually the final kick of the game.
South Africa (4-4-1-1): Khune; Gaxa, Mokoena, Khumalo, Masilela; Tshabilala, Dikgacoi, Letsholonyane (Moriri 57), Modise; Pienaar (Josephs 79); Mphela.
Uruguay (4-3-3): Muslera; M Pereira, Lugano, Godin, Fucile (A Fernandez 70); Arevalo Rios, Perez (Gargano 90), A Pereira; Cavani (S Fernandez 90), Forlan, Suarez.