Amad Diallo successfully netted both goals during the second half at Old Trafford, thereby bolstering United's prospects of progressing further in the tournament. Concurrently, Tottenham's hitherto unblemished record came to an end with a 3-2 defeat against Galatasaray.
The last time United triumphed in Europe was against Copenhagen in the Champions League on October 24 of the previous year.
"We discussed this in the dressing room, and it was essential to make a change, which we did," said Ruud van Nistelrooy, the interim head coach of United.
Diallo's first goal came in the 50th minute with a well-placed header that eluded PAOK goalkeeper Dominik Kotarski, followed by a deflected shot from outside the box that found the bottom corner in the 77th minute.
Under Van Nistelrooy's leadership, United has secured two wins from three matches, with one more game against Leicester on Sunday before he hands over the reins to Ruben Amorim.
It remains uncertain whether Van Nistelrooy will have a role after his interim period, but he is focused on positioning United favorably for Amorim's arrival.
Erik ten Hag was dismissed last week following a disappointing start to the season that left the team in 14th place in the Premier League and without a victory in the Europa League.
Amorim was swiftly appointed as his successor, but Van Nistelrooy has been tasked with managing the team while the Portuguese coach completes his notice period at Sporting Lisbon.
He has successfully guided the team to victories in both the English League Cup and the Europa League, alongside a draw against Chelsea in the league.
Victor Osimhen made a significant impact by scoring two goals within eight minutes, leading Galatasaray to a 3-2 victory over Tottenham in Turkey.
Osimhen netted his inaugural European goal for Galatasaray following his transfer from Napoli, delivering a precise low shot into the right corner to put the hosts ahead 2-1 in the 31st minute. He then added his second goal just eight minutes later, heading in a beautifully curled cross from Dries Mertens.
This match marked Tottenham's first defeat in the competition after securing three consecutive wins, while Galatasaray remains unbeaten with three victories and a draw.
All matches on Thursday began with a moment of silence to pay tribute to the victims of the severe flooding in Spain.
In Istanbul, Yunus Akgün opened the scoring for Galatasaray in the sixth minute, capitalizing on a poorly cleared free kick by Mertens, volleying the ball from outside the box past goalkeeper Fraser Forster.
Tottenham equalized in the 19th minute through Will Lankshear, who scored from close range during only his second senior appearance for the club, following a cross from Brennan Johnson. However, Lankshear received a second yellow card and was sent off in the 60th minute.
Dominic Solanke, who came on as a substitute, managed to score for Tottenham with a backheel finish in the 69th minute.
Lazio remains the only team with a perfect record, achieving four wins after Pedro Rodríguez scored in injury time to secure a 2-1 win over Porto.
Ajax showcased a dominant performance with five different players scoring in a 5-0 victory against Maccabi Tel-Aviv, while three substitutes contributed to Alkmaar's 3-1 win over Fenerbahce, marking the first loss of the competition for José Mourinho’s side.
Latvia’s RFS managed to earn a 1-1 draw against Anderlecht with a stoppage-time equalizer, marking the first dropped points for the Belgian team.
Earlier, Eintracht Frankfurt secured a 1-0 win over Slavia Prague thanks to a second-half goal from Omar Marmoush, while Roma was held to a 1-1 draw at Union Saint-Gilloise, adding to their disappointing results following a 3-2 loss to Hellas Verona in Serie A over the weekend.
Rangers played to a 1-1 draw against last year’s Conference League champions, Olympiacos.
Conference League
Chelsea achieved a remarkable 8-0 victory over Armenian side Noah, setting a new record for the largest win in the third-tier Conference League.
The team surged to a commanding 6-0 lead in the first half, with João Félix scoring twice, while Tosin Adarabioyo, Marc Guiu, Axel Disasi, and Mykhailo Mudryk each contributed a goal. Christopher Nkunku added two more in the second half, including a penalty.
The previous record was held by Nordsjaelland, who triumphed over Ludogorets with a score of 7-1 last season.
Chelsea is among six teams that have secured three victories in their first three matches.
In other matches, Vitória overcame Mladá Boleslav 2-1, Jagellonia triumphed over Molde 3-0, and Heidenheim defeated Hearts 2-0.
Earlier in the day, Legia Warsaw dominated Dinamo Minsk with a 4-0 win, while SK Rapid comfortably beat Petrocub 3-0.