La Celeste earned victory through Edinson Cavani's goal early in the second half, as the Paris Saint-Germain striker marked his 100th appearance by tapping home from close range.
Thirty-two years on from the only previous meeting between these two nations, both teams saw chances come and go but it was Uruguay - unlucky to hit the post twice in the first half - who did just about enough to pick up the trophy.
The tempo of the match was set early on as Luis Suarez took down a diagonal pass and unleashed a shot that came back off the woodwork, moments before Sam Vokes's first-time shot in the box was kept out by Fernando Muslera.
Matchwinner Cavani was unable to tap in Suarez's cross from a few yards out and Andy King twice picked out Muslera with Wales's latest attempts.
The South American nation were the ones steadily building momentum as the first half edged to its conclusion, with Suarez rounding Wayne Hennessey following an Ashley Williams error but somehow finding the upright and not the back of an empty net.
Cavani's powerful strike was kept out by Hennessey to delay him a 42nd goal on his 100th cap, but it was the Dragons who nearly snatched a half-time lead as Harry Wilson's deep free kick took a touch off Bale, forcing Muslera into a smart stop down low.
Just two places separate these nations in the latest FIFA rankings, and that told as they produced an entertaining first half, but it took just four minutes of the second half for Uruguay to edge in front.
PSG marksman Cavani bagged his landmark goal by converting from close range after Cristian Rodriguez was played in behind with a simple pass over the top, squaring the ball for his teammate to do the rest.
Cavani somehow missed an identical chance soon after, this time from a right-sided delivery, though Wales also had a chance as King's latest shot drifted just wide - Vokes unable to get a telling touch.
Ryan Giggs went with an unchanged starting lineup on the back of the 6-0 win over China, though the second half saw a number of subs brought on, including first caps for Swansea City youngster Connor Roberts and Bristol Rovers attacker Billy Bodin.
Momentum was something Wales struggled with after going behind, not helped by the five alterations, seeing yet another King shot miss the mark and substitute Lee Evans's hit collected by Muslera when it was likely dropping wide.
Skipper Williams's header inside the box lacked power from the Dragons' last half-chance of the match, meaning just a fourth defeat in 18 matches for Wales in Giggs's second game in charge.
WALES XI (3-4-3): Hennessey; Chester (Lockyer 79'), Williams, Davies (Hedges 90'); Gunter (Matthews 79'), King, Allen, John (Roberts 59'); Wilson (Evans 72'), Vokes (Bodin 67'), Bale
URUGUAY XI (4-3-1-2): Muslera; Varela, Godin, Gimenez (Coates 8'), Laxalt; Nandez (Stuani 85'), Bentancur (Silva 78'), Vecino; Rodriguez (Torreira 70'); Cavani (Gomez 93'), Luis Suarez