The Manchester United midfielder broke the deadlock in a scrappy Group H clash when his 54th-minute cross, which was aimed at Cristiano Ronaldo, nestled in the far corner.
He then wrapped up the points with a stoppage-time penalty and almost had a hat-trick as Fernando Santos' side joined France and Brazil in sealing their passage to the knockout stages with a game to spare.
The win saw Portugal avenge their 2-1 defeat by Uruguay in the last 16 of the 2018 competition in Russia.
Chances did not fall freely during the opening half-hour, with neither side registering a shot on target. William Carvalho's sweetly struck volley was just too high, while Jose Gimenez sent a looping header narrowly over the crossbar.
The game's first attempt on target in the 32nd minute almost provided one of the goals of the tournament when Rodrigo Bentancur embarked on a jinking run through the Portugal defence.
But the Uruguay midfielder's finish let him down, as he shot straight at Diogo Costa when clear on goal.
La Celeste were aiming to become the first nation to record six straight clean sheets in the World Cup group stages, but they were given a warning when Joao Felix hit the side netting in the 51st minute.
Fernandes then opened the scoring three minutes later when his attempted centre, which Ronaldo initially appeared to faintly connect with, evaded Sergio Rochet.
Uruguay looked to respond as Maximiliano Gomez rattled the post and Luis Suarez hit the side netting, but Portugal sealed victory when Fernandes, who was involved in winning the penalty, calmly slotted home from 12 yards after VAR penalised Gimenez for handball.
Fernandes twice went close to completing his hat-trick in the dying moments, Rochet saving his volley before he rattled the woodwork from 20 yards.
For only the third time in their World Cup history, Portugal have won their opening two group games at the finals.
A good omen is that on both previous occasions – 1966 and 2006 – they went on to reach the semi-finals.
Uruguay have failed to score in three consecutive World Cup games for only the second time ever and go into matchday three sitting bottom of the group.
Fernandes at the double
It was a unique brace for Fernandes - FIFA initially credited his first goal to Ronaldo, who insisted he had got a touch – before ruling in the midfielder's favour.
Fernandes' double came from a game-high six shots, while his tally of 83 touches was also the highest recorded and no player registered more touches in the opposition box (five) or crosses (five, level with Guillermo Varela) than the United midfielder.
He has been directly involved in eight goals in his last five Portugal appearances (scoring five and assisting three), hitting form at international level at an ideal time.
Edinson Cavani, who netted twice when these nations met in Russia four years ago, was restored to the starting line-up ahead of Luis Suarez.
However, the veteran striker registered just one shot on goal – an early second-half volley he dragged wide – while no starting player had fewer touches than him (21).
Key Opta Stats:
- Portugal have now scored in each of their last eight World Cup games, their best-ever run in the competition.
- Only Brazil (0) and Ecuador (1) have faced fewer opposition shots on target at the 2022 World Cup than Uruguay (3), who conceded with two of the three they faced in this game.
- Portugal tasted victory against a South American side in the World Cup for the first time since 1966 (3-1 v Brazil).
- At 39 years and 275 days old, Portugal defender Pepe became the third-oldest outfield player in World Cup history, behind only Roger Milla (42y, 39d) and Atiba Hutchinson (39y, 292d).