The Portugal international, who had never previously failed from 12 yards for United, looked to have passed up the visitors' best chance of victory at St James' Park when Karl Darlow produced a magnificent stop.
That spot-kick came after Harry Maguire - fit despite a knock on international duty - cancelled out a second-minute Luke Shaw own goal, with United dominant but set to be frustrated heading into the closing stages.
A rapid counter-attack produced the breakthrough moment, though, as Fernandes picked out the top-right corner before Aaron Wan-Bissaka lashed in a third and Marcus Rashford finished the 96th-minute fourth, ensuring United bounced back from the 6-1 defeat to Tottenham with all three points.
The latest setback in Shaw's United career had come after just 102 seconds as he toed Emil Krafth's cross past David de Gea following a Newcastle counter.
It was a goal befitting a ragged start as United dictated without initially threatening, finding their range after 19 minutes only for Fernandes' stunning strike to be ruled out due to an offside in the build-up.
The visitors had their leveller four minutes later, though, as captain Maguire - who missed from point-blank range at the same end of the stadium last season - headed in Juan Mata's corner.
De Gea saved well from Allan Saint-Maximin's piledriver, while Darlow dealt with Wan-Bissaka's wayward cross but was then grateful to Jamaal Lascelles for a goal-line clearance from Rashford, who saw another shot parried.
Only a sublime stop from De Gea denied Callum Wilson from close range early in the second half, yet Newcastle survived an even greater scare when Jamal Lewis fouled Rashford but Darlow brilliantly repelled Fernandes' spot-kick.
Jonjo Shelvey nodded another Maguire header away from the line moments later and Darlow came to the hosts' rescue again with a brave block from Rashford.
It looked like that would be enough to preserve a home point until United's late show as Fernandes applied a wonderful finish with four minutes left, before Wan-Bissaka rifled into the roof of the net and finally Rashford swept in number four with time up.
What does it mean? Patience pays for Solskjaer's side
This did not look like being United's day as Darlow came through a slightly shaky start to deny Ole Gunnar Solskjaer's men time and again.
The Newcastle goalkeeper, who was hobbling in the closing stages after a challenge with Rashford, made eight saves in all from 28 United attempts - 14 on target - but was helpless in a frantic finale.
Rashford showed poise to tee up Fernandes and also Wan-Bissaka before belatedly scoring himself, sealing a win that was a lot less comfortable than the scoreline suggests.
116 - Aaron Wan-Bissaka is the 116th different player to score for Manchester United in the Premier League in what is his 38th league appearance for the club. Devilish. pic.twitter.com/IfIjrlIGUu— OptaJoe (@OptaJoe) October 17, 2020
Maguire makes amends
Newcastle appear to be incapable of dealing with Maguire, who now has two goals against the Magpies - one for Leicester City - and should have had another last year when left unmarked in the six-yard box.
After tough recent outings for both club and country, the United skipper also did his job at the other end, making three clearances and four interceptions.
Last straw for Shaw
Shaw's days as United's first-choice left-back looked numbered even before this mishap. Alex Telles, signed after the England man's woeful display against Tottenham, watched on from the bench.
It was a half-hearted attempt at blocking Krafth's centre that deceived De Gea, and Shaw was perhaps fortunate Newcastle opted not to isolate him against Saint-Maximin, who created two chances from the opposite flank.
Key Opta Facts:
- Newcastle United conceded four goals at home in the Premier League for the first time since April 5, 2014 - also against Manchester United (4-0 defeat).
- Man Utd enjoyed their 10th comeback win against Newcastle in the Premier League - the most by any side against a single opponent in the competition.
- Ole Gunnar Solskjaer's side have been awarded 17 penalties in the Premier League since the start of last season, which is five more than any other side in the competition (12 scored).
- Bruno Fernandes has been directly involved in 20 goals in his 18 Premier League appearances for Man Utd (11 goals, nine assists), scoring in each of his last three games.
- Marcus Rashford registered three goal involvements in a single Premier League game for the only the third time ever (one goal, two assists), having also done so against Fulham in December 2018 and Arsenal in February 2016.
This was a much-needed win for United ahead of a pivotal stretch. They visit Paris Saint-Germain in the Champions League on Tuesday, while Newcastle are not back in action until next Sunday's trip to Wolves.