The Red Devils edged a close contest with the Cypriot side 3-2 in last week's showdown, but the unfancied visitors sure did give the 20-time English champions quite the scare.
Match preview
Coming up against a somewhat familiar foe in Neil Lennon, Man United fans who braved the journey to Omonia last week may have been preparing for another miserable journey home when Karim Ansarifard gave the Cypriot champions a 1-0 lead before the break.
However, Erik ten Hag's alterations paid dividends to the maximum last week, as a brace from Marcus Rashford alongside a strike from fellow substitute Anthony Martial turned the game on its head before Nikolas Panagiotou added another consolation for the hosts.
Another come-from-behind job was on the agenda when Man United resumed Premier League duties at a steadfast Everton side, who went ahead through Alex Iwobi before Antony and Cristiano Ronaldo responded for Man United just before half time.
With their dismal start to the campaign now a distant memory, Man United are now firmly in the Champions League conversation - sitting fifth in the Premier League table - while their six-point haul from three Europa League games is good enough for second in Group E behind a perfect Sociedad side.
Nine goals conceded from their last three games in all competitions will come as a concern to Ten Hag, although defensive absentees have played a significant part in that, and the Red Devils - who have gone down to Atletico Madrid and Sociedad in their last two European home games - have never lost three continental matches on the bounce at Old Trafford.
While Omonia can be lauded for troubling the Man United defence in front of their ardent fanbase last week, spirit and passion does not win points, and the Cypriot champions are still without a single one of those at the halfway point in the group stage.
Lennon's men have scored just three goals and conceded eight in successive losses to Sheriff Tiraspol, Real Sociedad and now Man United to languish in fourth place in the section, and any slim hopes the visitors had of finishing in the top two could be extinguished with defeat this week.
It is not impossible for Omonia to usurp Sheriff Tiraspol in the Europa Conference League spot - there is only three points in it - but Lennon's side could not rediscover their momentum at the weekend as they lost 1-0 to AEL in First Division action.
Defeat to AEL marked a fourth loss from five away fixtures for Omonia, who have not won a European game on the road since defeating Shamrock Rovers in 1987 - one of only two victories away from home for the Cypriot side on the continent.
If Lennon's side are to produce a seismic shock and blow Europa League Group E wide open against Man United, they must do what no other side from Cyprus has done before - win an away game against an English club.
Manchester United Europa League form:
L
W
W
Manchester United form (all competitions):
W
L
W
L
W
W
Omonia Europa League form:
W
W
L
L
L
Omonia form (all competitions):
Team News
The luckless Martial had only just begun to work his way into Ten Hag's good books before coming off with a back problem against Everton, so Ronaldo is in with a strong chance of featuring from the off again after putting in his strongest showing of the season so far at Goodison Park.
Axel Tuanzebe, Brandon Williams and Aaron Wan-Bissaka remain absent for Man United, and doubts persist over the availability of Harry Maguire and Donny van de Beek, but Raphael Varane was fit enough to appear as a substitute in the win over Everton.
Varane could now re-form his partnership with Lisandro Martinez, who is one booking away from a Europa League suspension, while Marcus Rashford can expect to keep Jadon Sancho at bay on the left-hand side again.
Meanwhile, Omonia also have a player one yellow card away from suspension in the form of centre-back Adam Lang, but the Hungary international is in no danger of losing his place in Lennon's backline.
Panagiotou's goal in last week's showdown may not be enough to see him displace the more experienced Hector Yuste, and Lennon was forced to bring off goalkeeper Fabiano in the 57th minute against AEL - Konstantinos Panagi should now come in from the off.
Former Manchester City youth product Brandon Barker was a starter in last week's loss to Man United, but he was dropped to the bench at the weekend as Loizos Loizou and Fotis Papoulis both aim to hold their spots.
Manchester United possible starting lineup:
De Gea; Dalot, Varane, Martinez, Shaw; McTominay, Eriksen; Antony, Fernandes, Rashford; Ronaldo
Omonia possible starting lineup:
Panagi; Miletic, Lang, Yuste; Matthews, Charalampous, Diskerud, Lecjaks; Loizou, Ansarifard, Bruno
We say: Manchester United 2-0 Omonia
Ten Hag was forced to look to the bench to get the job done against Omonia last week, but the Red Devils should not face any similar difficulties against their visitors this week, especially if Lennon is without his first-choice goalkeeper.