Two more goals in the last 10 minutes, a header from Brazilian-born forward Eder and a Daniele De Rossi penalty, condemned the South Americans to their fifth successive defeat while Italy extended their unbeaten run to nine games.
It was the first meeting between the two sides since their controversial match at the 2014 World Cup when Uruguay forward Luis Suarez bit Italy defender Giorgio Chiellini.
The incident was missed by match officials but Suarez was subsequently suspended from football for four months and banned for nine competitive internationals.
Uruguay's 1-0 win meant that Italy were knocked out in the group stage, prompting the resignations of both coach Cesare Prandelli and federation president Giancarlo Abete.
Suarez missed Wednesday's game through injury while Chiellini came on as a substitute in the second half.
Italy were gifted a seventh minute lead when Lorenzo Insigne launched a long ball forward, Andrea Belotti chested it down with his back to goal and Gimenez took it off his foot but inadvertently rifled a shot past goalkeeper Fernando Muslera.
Italy had several promising attacks without further troubling Muslera before halftime.
Uruguay, also missing their other key forward Edinson Cavani through injury, took control in the second half and penned Italy into their half.
Uruguay's Martin Caceres headed the ball into the net on the hour but it was harshly disallowed for a foul on Riccardo Montolivo.
Eder diverted Manolo Gabbiadini's shot into the goal with a close-range header in the 83rd minute and De Rossi scored from a penalty in stoppage time after Stephan El Shaarawy was tripped by the hapless Gimenez.
Italy midfielder Claudio Marchisio, sent off in the World Cup match, suffered another misfortune when he limped off injured midway through the first half.
(Writing by Brian Homewood; Editing by Toby Davis)
