Goals from Jonathan Walters, Cyrus Christie and substitute James McClean sealed the victory at the Aviva Stadium despite Jose Gimenez’s first-half equaliser.
Martin O’Neill made eight changes from the 3-1 defeat against Mexico in New Jersey as Burnley defender Kevin Long made his first start for Ireland.
Ireland dominated much of the occasion with opponents Uruguay hit with an injury blow in the 11th minute as PSG striker Edinson Cavani went off injured.
A minute later, Brighton and Hove Albion defender Shane Duffy went close as a one-two from a right-sided corner saw Robbie Brady cross towards the back-post but Duffy couldn’t make contact.
Just before the half-hour, Ireland took the lead and in some style. Surrounded by three players, captain Walters turned 20-yards out and curled the ball over the keeper into the top right-hand corner.
Uruguay almost hit back shortly afterwards as Martin Caceres rose highest to head a right-sided corner against the bar with goalkeeper Darren Randolph beaten in the 33rd minute.
Randolph was beaten four minutes later. Carlos Sanchez swung a 40-yard free-kick towards the penalty spot and as Randolph ran out to punch, Gimenez beat him to the ball as it looped into the net off his shoulder to level the tie.
However, Ireland should have been ahead at the break. A fantastic move saw Cyrus Christie find the on-rushing Brady at the back-post with a diagonal ball and he played it across for Walters who somehow hit the bar from three yards out.
Five minutes after the break, Ireland did get the second goal their play deserved. The impressive Christie received the ball on the right and despite having two defenders in front of him, he turned inside and from the edge of the area, he found the bottom corner with a left-footed finish.
Ireland sealed the win with 14 minutes remaining and in some style. On the pitch for just four minutes after coming on for Jeff Hendrick, McClean ran onto Daryl Murphy’s through-ball and after beating Gimenez to the ball, the Derry man smashed the ball home into the bottom right-hand corner.
Republic of Ireland: Darren Randolph (Keiren Westwood ’46), Cyrus Christie, Glenn Whelan (Wes Hoolahan ’46), Robbie Brady, Jeff Hendrick (James McClean ’72), Stephen Ward, Kevin Long, Jonathan Walters (Daryl Murphy ’59), Shane Duffy (Alex Pearce ’59), Harry Arter, Jonny Hayes (Aiden McGeady ’59).
Uruguay: Esteban Conde, Jose Gimenez, Carlos Sanchez, Diego Laxalt, Jonathan Urretaviscaya, Matias Vecino, Maximiliano Pereira (Federico Ricca ’61), Egidio Arevalo Rios, Sebastian Coates, Edinson Cavani (Cristhian Stuani ’11), Martin Caceres.
Referee: Craig Thompson (Scotland).