The Europeans had dominated possession before Fernandes' 54th-minute cross floated past Uruguayan goalkeeper Sergio Rochet, who was rooted to the spot as Cristiano Ronaldo rose to head the ball and initially celebrated the goal as his.
Fernandes scored the second in injury time after a penalty was awarded for handball following a video review.
Uruguay, who had knocked Portugal out of the 2018 World Cup, will rue a string of chances on the break: midfielder Rodrigo Bentancur skipped past three players only to see his shot brilliantly saved, Maxi Gomez hit the post and Luis Suarez shot into the side netting.
Portugal's second win in two games put them on top of Group H with six points, heading into the last 16. Uruguay, third by one point, must beat Ghana in their final group game to progress.
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