Alex Baena’s weak shot slipped through Muslera’s grasp for the only goal as Spain avoided a last 32 showdown against Argentina.
The European champions will instead face Austria or Algeria next in Los Angeles on Thursday.
Uruguay’s defeat allowed debutants Cape Verde to secure second place and a meeting with Lionel Messi and the defending champions thanks to a 0-0 draw against Saudi Arabia.
Two-time winners Uruguay become the highest ranked side to crash out in the group stages as the defeat rounded off a miserable tournament for Marcelo Bielsa and his squad.
After draws against Cape Verde and Saudi Arabia, reports of a revolt in the Uruguay camp emerged with leading players, including Real Madrid’s Federico Valverde, clashing with Bielsa over his tactics.
Spain’s King Felipe was among those in attendance but the only clash between two former winners of the World Cup in the group stages was a huge disappointment.
Lamine Yamal’s to the starting line-up had sparked the Spanish attack into life in a 4-0 thrashing of Saudi Arabia after La Roja began in underwhelming fashion with a goalless draw against Cape Verde.
But another laboured attacking performance leaves Luis de la Fuente with plenty to ponder before the knockout stages begin on Sunday.
A hero of Uruguay’s run to the semi-finals in 2010, Muslera was at fault for both Cape Verde’s goals in a 2-2 draw.
And in Guadalajara, Spain had barely threatened the Uruguay goal before the 40-year-old allowed Baena’s shot to dribble over the line from Marcos Llorente’s cross on 42 minutes.
To rub salt into Urguayan wounds, Manchester United midfielder Manuel Ugarte was injured in the build-up to the goal and stretchered off with what appeared a serious knee injury.
Bielsa replaced Muslera at half-time with Sergio Rochet and the Uruguay boss made an even bolder call when Valverde was taken off on the hour mark.
De la Fuente also turned to his bench and the introduction of Dani Olmo and Fabian Ruiz finally injected some life into the Spanish performance.
Olmo should have done better when he spooned a shot over from a rare flash of Yamal’s brilliance to tee up his Barcelona team-mate.
Yamal was replaced 15 minutes from time as his minutes continue to be managed after a hamstring injury ended his club season prematurely.
His replacement Ferran Torres should have doubled the lead five minutes from time but hit the bar with just the goalkeeper to beat.
Uruguay’s miserable tournament was summed up when Agustín Canobbio was shown a straight red card in stoppage time for a wild lunge on Pau Cubarsi.
Hyped as one of the pre-tournament favourites, Spain are now 34 competitive games unbeaten and are yet to concede a goal at the World Cup.
But in stark contrast to some of the scintillating attacking play on show from the likes of France, Argentina and the Netherlands, La Roja are yet to convince in their quest for a second World Cup triumph. (AFP)
