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Fernandes scored with a cross intended for Cristiano Ronaldo that sailed into the net on 54 minutes. He then converted a spot kick in added time to put his side into the knockout stages with one match remaining.
Portugal had the lion's share of the possession and dominated for most of matchday nine's Group H match, but struggled to create clear-cut chances until the second half in a game where Uruguay looked jaded and out of sorts.
It is the third time at a World Cup that Portugal has won two successive group-stage matches - the previous two occasions led to streaks into the semi-finals.
Portugal looked threatening in possession but struggled to create scoring chances, with Bernardo Silva, Fernandes and Joao Felix frustrated in front of goal early on.
But it was Uruguay who had the best chance of the half 32 minutes in when Rodrigo Bentancur picked up the ball and ran half the length of the field, skipping around three defenders before firing off a low shot that was blocked by the advancing keeper Diogo Costa.
Bentancur was at the centre of the action again a few minutes later when his outstretched leg met a cross from the left from Mathias Olivera, trickling through to Darwin Nunez who failed to convert from close range.
Portugal battled hard for a goal and Felix came close on 52 minutes when he blasted low into the side netting.
They finally broke the deadlock two minutes later when Fernandes' 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.
Uruguay had a brief rally to try to get back into the match after a raft of substitutions, with Facundo Pellistri making an instant impact, Luis Suarez coming close and Maxi Gomez hitting the post.
But the match belonged to Portugal and Fernandes, who coolly converted a penalty in added time after a handball in the box that required a VAR review.
Hungry for more, the Manchester United midfielder almost ended with a hat-trick in the dying seconds, with one effort saved at the near post by Rochet and another strike that cannoned off the post.
Tune in on Saturday as Korea Republic take on Portugal and Ghana face Uruguay in their final decisive matches of the Group stage.
Saturday, December 3
Group H - Korea Republic v Portugal
1.30am - 4:30am (AEDT) - kickoff at 02.00am
LIVE on SBS and SBS On Demand
Group H - Ghana v Uruguay
1:30am - 4:30am (AEDT) - kickoff at 02.00am
LIVE on SBS VICELAND and SBS On Demand
