Uruguay goalkeeper Fernando Muslera saved spot kicks from Ghana captain John Mensah and Dominic Adiyiah as the South American side qualified for the semifinals of the World Cup for the first time in 30 years.
Uruguay won the penalty shoot-out with 4 shot to 2 at Soccer City on Friday night.
The teams were locked at 1-1 after regulation time, with no goals scored in 30 minutes of extra time.
Midfielder Sulley Muntari scored for Ghana with a superb strike from 35 metres in first-half injury time, and striker Diego Forlan, the Man of the Match, equalised for Uruguay with a direct free kick in the 55th minute.
Uruguay will face The Netherlands in the first semi-final in Cape Town next Tuesday.
