Edinson Cavani bagged a brace to beat Portugal 2-1 and then limped off injured, as Uruguay will face France in the quarter-final.
There were plenty of Serie A representatives in the 22 starting in Sochi, including Matias Vecino, Rodrigo Bentancur, Lucas Torreira, Diego Laxalt, Martin Caceres and Joao Mario, but Milan forward Andre Silva was dropped to the bench.
Uruguay took first blood with a sensational diving header from former Napoli and Palermo striker Edinson Cavani on the end of a Luis Suarez cross at the back post.
Rui Patricio beat away a long-range Suarez free kick that he drilled through the wall, but Portugal came out fighting for the second half.
A short corner was then whipped in for the towering header of defender Pepe and it was the first goal Uruguay conceded in this World Cup.
However, as Portugal were pressing hard, Uruguay struck on the counter with a Rodrigo Bentancur assist and Cavani curling a magnificent first-time finish from the edge of the box off the inside of his right boot.
Ex-Lazio goalkeeper Fernando Muslera almost threw it all away by fumbling a Raphael Guerreiro cross, but Bernardo Silva blasted the loose ball over an open goal.
Moments later, Cavani limped off with a muscular problem – aided by Cristiano Ronaldo – and Uruguay shut up shop under wave after wave of Portuguese attacks. In fact, Cristian Rodriguez wasted a golden opportunity to add a third goal on the counter when he stumbled.
Cristiano Ronaldo's final contribution in stoppages was to get booked for dissent and he'd be suspended for the next game - but it won't be the World Cup quarter-final.
Uruguay 2-1 Portugal
Cavani 7, 62 (U), Pepe 54 (P)
Uruguay: Muslera; Caceres, Gimenez, Godin, Laxalt; Nandes (C Sanchez 81), Torreira, Vecino, Bentancur (C Rodriguez 63); Suarez, Cavani (Stuani 74)
Portugal: Rui Patricio; Ricardo, Pepe, Fonte, Raphael; Bernardo, William, Adrien Silva (Quaresma 65), Joao Mario (M Fernandes 84); Guedes (Andre Silva 74), Cristiano Ronaldo
Ref: Ramos (MEX)