United were caught on the counter as Karim Ansarifard fired home a lovely opener late in the first half, but the introductions of Rashford and Martial in the second half set things right for Erik ten Hag's side as the duo dragged United to three points.
Omonia had ten men behind the ball early on and it took United around ten minutes to manage their first real opportunity. Christian Eriksen played through Antony and the ball found its way to Cristian Ronaldo, whose low drive brought an excellent save out of Omonia stopper Fabiano.
Antony then declined to shoot when one-on-one and instead cut the ball back to Bruno Fernandes, but his pass was behind the Portugal international and the danger was cleared.
Just seconds later, Fernandes hit the bar with a nice lobbed half-volley, before Fabiano pulled out another impressive save to repel a curling effort from Antony.
United threw everything at Omonia to get ahead but were punished 34 minutes in when they sent nine men forward for a free-kick. The last line of defence, Tyrell Malacia, gave the ball away in the Omonia half and the Cypriots countered into an empty United half, with Ansarifard firing past David de Gea to give the hosts a shock lead heading into the break.
Rashford, on to replace Jadon Sancho at the break, tied things up seven minutes into the second half with a delightful strike from the edge of the penalty area.
Martial joined the fun on the hour mark and got himself on the scoresheet just moments after coming on. Combining with Rashford, the Frenchman picked the ball up on the edge of the box and drilled a low effort down into the bottom corner.
The substitutions put United firmly in the ascendency but Omonia nearly had an equaliser through Bruno, who beat the offside trap but couldn't get the connection needed to lob De Gea.
With just over ten minutes to go, it looked like Cristiano Ronaldo would finally grab his 700th club goal when a cut-back from Diogo Dalot gifted him almost an open goal, but the veteran forward could only watch as his strike cannoned back off the post.
He may not have scored, but Ronaldo bagged an assist for a second goal from Rashford five minutes from time. It may have been a shot from the Portuguese, but it found its way to the substitute who tapped into an empty net.
With the celebrations still ongoing, Omonia pulled one back through Nikolas Panayiotou after some sloppy play out from the back from United, who only had themselves to blame for setting up a nervy finish.
Ronaldo and Rashford both fluffed counters which would have killed the game off, but United held on to secure all three points.
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