The 84th-ranked Europeans put up a good fight on Friday but were finally breached by the Copa America holders as the second half wore on
Substitute Stuani netted the decisive goal on the hour-mark to lift Uruguay to victory against an under-strength Northern Ireland team in Montevideo.
The Espanyol man replaced veteran striker Diego Forlan at half-time and his introduction worked wonders as the sixth-ranked nation stepped up preparations for the World Cup in Brazil, where they will come up against Italy, England and Costa Rica in Group D.
Uruguay, who had drawn their past two competitive games heading into Friday's clash, extended their unbeaten home streak to 13 matches.
Minus injured star striker Luis Suarez, Oscar Tabarez named close to a full-strength team, with Edinson Cavani, Diego Forlan, Maximiliano Pereira and Gaston Ramirez among the starters for Uruguay's first match against Northern Ireland on home soil.
While Northern Ireland were without key men Jonny Evans, Chris Brunt, Kyle Lafferty and Paddy McCourt.
The two countries had gone head-to-head on three previous occasions, with their most recent clash a 1-0 victory for Uruguay in New Jersey in 2006.
But despite their superior standing in the Fifa world ranking, Uruguay were limited to just long-range efforts during the opening 15 minutes.
The home side were even out-passed by Northern Ireland at stages of the first half and their frustrations began to show, with tough-tackling midfielder Walter Gargano shown a yellow card for a late challenge in the middle of the pitch.
Uruguay were eventually presented with an avenue to goal after the ball fell to the feet of both Cavani and Forlan in the 32nd minute but they were sensationally denied by Olympiakos goalkeeper Roy Carroll.
Northern Ireland turned over possession outside the penalty area and Uruguay pounced with Cavani attempting to guide his low effort past Carroll, who parried the ball in the direction of Forlan.
With an open goal gapping, Forlan had the opportunity to break the deadlock and close to within one goal of Uruguay's all-time scoring record held by Suarez (38) but Carroll did well to dive low and push the ball away for a corner.
Forlan came close again on the stroke of half-time, unleashing a tricky shot from distance, which cannoned off the chest of Carroll and dropped to Cavani, but the Paris Saint-Germain striker blazed his effort wide of the post to leave the game on level terms at the break.
That proved to be Forlan's final contribution after he was replaced by Stuani at half-time, while Jose Gimenez came on for defender Sebastian Coates.
Coates' exit seemed to disrupt Uruguay, who were caught out at the back but Northern Ireland failed to make the most of a two-on-one situation.
But having matched Uruguay for the most part, Michael O'Neill's men were made to pay in the 61st minute when Stuani reacted quickest inside the penalty area to finally breach the Northern Ireland goal.
After Cristian Rodriguez dazzled his way inside the box, the ball found its way to Cavani, who squared to Stuani to smash home within 15 minutes of being brought on.
The hosts dominated from that point with several chances falling their way, though they were unable to add to their advantage as Northern Ireland's winless streak stretched to seven games.
Uruguay return to Estadio Centenario for Wednesday's fixture against Slovenia before flying out to Brazil for their opening World Cup game against Costa Rica on June 14.