A slow start from the Red Dragons was capitalised on by their 19th-in-the-world opponents, but a hat-trick of tries from Cory Allen helped his side well on their way to a bonus-point win.
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The Southern Hemisphere minnows, competing in this showpiece competition for the first time since 2003, made a dream start to the contest by successfully kicking over two pens inside the opening 10 minutes.
Felipe Berchesi held his nerve to punish a Wales side lacking any discipline and showing some early tournament jitters, leaving the weakened home outfit with some work to do.
Buoyed by a now-boisterous backing in South Wales, the Red Dragons rallied and were finally rewarded when the returning Samson Lee dived over at the end of a strong maul, before Rhys Priestland - on kicking duties this afternoon - added the extras.
Allen touched down for a second soon after, giving Wales just a little breathing space in the first-ever Test meeting between the teams, and once more Priestland made no mistake from the follow-up.
Uruguay showed yet again that they should not be completely written off in Pool A, however, adding three more points via the boot of Berchesi - who at the same time equalled the best individual points record by a Teros player at the World Cup - to close the gap once more.
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Wales still had time to make things slightly more comfortable heading into the break, though, thanks to a second try of the clash from Allen.
The Cardiff Blues centre, without an international score to his name prior to today, was picked out by Priestland at the end of a sweeping move to push his side closer to that previous bonus-point triumph with 30 minutes on the clock.
There was more joy to come for Allen, as with two minutes of overtime played he successfully charged through the Uruguay backline to edge Warren Gatland's men further ahead and complete an impressive personal hat-trick of tries.
It was the 2011 semi-finalists who had the better of the early exchanges following the restart, too, though they were made to wait until 10 minutes in before bagging a fourth score.
Wales, breaking from an opposition lineout, made big strides and were able to keep the momentum alive through Hallam Amos, before Priestland split the sticks for a fourth time.
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With attention switching ahead to next weekend's potentially pivotal showdown with England at Twickenham, Gatland would have been concerned to see a number of players hobble off, including hat-trick hero Allen on the 54-minute mark.
Yet the Red Dragons were not finished there, adding three more tries before the contest was out, the first of which came on the back of another rolling maul which Gareth Davies - the first scrum-half to produce a try in this year's tournament - profited from.
Priestland was unsuccessful with his conversion on this occasion, but it did not appear to matter when Scott Williams looked for all the world to have himself crossed the whitewash, only for the TMO to adjudge that Amos' initial pass had been thrown forward.
Justin Tipuric then joined the party in the final 10 minutes when, yet again, a rolling Welsh maul ended with the hosts adding another five points to their growing score.
Davies rounded off the try-scoring in the dying stages to put the icing on the cake for Wales, setting up a likely make-or-break meeting with England in six days' time.