The small South American nation defied logic to bundle Ghana out of the World Cup after Asamoah Gyan missed a last gap penalty to send the game into penalty shoot-out.
Sulley Muntari put the Ghanaians ahead with a sleek finish on the stroke of the first half before Diego Forlán pulled parity on 54 minutes.
Gyan, who a penalty specialist, was handed the chance to send the Africans into the last four after Luiz Suarez was sent off for preventing a goal bound with his hand.
Ghana captain Stephen Appiah protested against the referee's decision to award the penalty, insisting a goal should have been awarded.
With vuvuzelas reverberating the Soccer City stadium in Johannesburg, the iconic Ghana striker hit the cross bar to send Africans fans into "coma".
Uruguay went on to clinch a semi-final berth after edging Ghana past the penalty shoot-out.
WORLD SOUTH AFRICA 2010
URUGUAY 1: 1 GHANA
(Uruguay won 4: 2 in the definition by penalties).
Field: Soccer City Stadium, Johannesburg (South Africa).
Referee: Olegário Benquerença. Assistants: José Cardinal and Bertino Miranda (Portugal).
URUGUAY: Fernando Muslera, Maximiliano Pereira, Diego Lugano (37 ′ Andrés Scotti), Mauricio Victorino, Jorge Fucile, Alvaro Fernández (45 ′ Nicolás Lodeiro), Diego Pérez, Egidio Arévalo Ríos, Edinson Cavani (75 ′ Sebastián Abreu), Diego Forlán , Luis Suárez. Technical director: Oscar Tabárez. Substitutes: Juan Castillo, Martín Silva, Diego Godín, Martín Caceres, Alvaro Pereira, Walter Gargano, Sebastián Eguren, Ignacio González, Sebastián Fernández.
GHANA: Richard Kingson, John Paintsil, Issac Vorsah, John Mensah, Hans Sarpei, Anthony Annan, Kwadwo Asamoah, Samuel Inkoom (73 ′ Stephen Appiah), Kevin-price Boateng, Sulley Muntari (87 ′ Dominic Adiyiah), Asamoah Gyan. Technical director: Milovan Rajevac. Substitutes: Daniel Agyei, Stepehn Ahorlu, Ibrahim Ayew, Kee Addy, Derek Boateng, Prince Tagoe, Matthew Amoah, Quincy Owusu-abeyie.
Goals: 45 ′ Sulley Muntari (G), 54 ′ Diego Forlán (U).
Incidence: At 120 ′ Asamoah Gyan's penalty kick (G) hit the horizontal.
Expelled: 120 ′ Luis Suárez (U).
Definition by penalties:
Diego Forlán (U) goal; Asamoah Gyan (G) goal; Mauricio Victorino (U) goal; Stephen Appiah (G) goal; Andrés Scotti (U) goal; John Mensah (G) saved Muslera; Maximiliano Pereira (U) finished off; Dominic Adiyiah (G) saved Muslera; Sebastián Abreu (U) goal.