The Cypriots surprisingly won 2-0 in Belgium last week, so can even afford a narrow defeat in the second leg and still progress.
Match preview
Indeed, very few neutrals would have predicted Omonia running out 2-0 winners at Gent's Ghelamco Arena, but that is exactly what they pulled off courtesy of strikes from Charalambos Charalambous and Brandon Barker either side of half-time.
Neil Lennon, who replaced former Manchester United defender Henning Berg as head coach, has transformed The Queen's form since taking over in March earlier this year. After Berg had overseen Omonia's first bottom-half finish in Cyprus' First Division in almost 70 years, Lennon resurrected their season by triumphing in the domestic cup.
That was Omonia's first domestic cup success in a decade and has put them on the brink of reaching the group stage of European competition for the third successive season. However, last time out they failed to win a single game in the maiden Europa Conference League, so the Europa League represents a major step-up in class.
Lennon will be determined to safeguard his players from any complacency despite last week's excellent performance and result, as an early goal for the away side could dramatically alter the course of the tie.
Generally speaking, Gent have more European pedigree than Omonia, having competed in the Champions League group stage as recently as the 2015-16 season.
While a fifth-placed finish in the Belgian First Division was representative of their gradual decline in recent years, Hein Vanhaezebrouck would have expected a much better showing than his side's 2-0 loss in Cyprus last Thursday.
Chasing the game after Charalambous's opener, they left themselves far too open to a sucker-punch in transition when chasing the game, which is exactly what Barker achieved by doubling his side's lead with less than 15 minutes to go.
The extent of the defeat has put huge pressure on Vanhaezebrouck's players' shoulders to turn the tie around, with De Buffalo's facing the prospect of not featuring in a European group stage for the first time since the 2018-19 campaign.
Omonia Europa League form:
Omonia form (all competitions):
Gent Europa League form:
Gent form (all competitions):
Team News
Lennon is unlikely to change a winning team after such an impressive result and performance in Belgium last week.
That means Barker may be called upon to make an impact from the bench once again having bagged what could be a decisive goal in the tie late on.
Gent, meanwhile, may turn to former Porto striker Laurent Depoitre to lead the line having only utilised him from the bench last week.
Alessio Castro-Montes could make way, with Hugo Cuypers taking up a wider starting berth.
Omonia possible starting lineup:
Fabiano; Miletic, Yuste, Panagiotou; Matthews, Diskerud, Charalampous, Bachirou, Lecjaks; Bruno, Kakoullis
Gent possible starting lineup:
Roef; Hanche-Olsen, Ngadeu, Torunarigha, Fortuna; Hong, Kums; Cuypers, Hjulsager, Hauge; Depoitre
We say: Omonia 1-2 Gent
We can envisage Gent coming close to turning the tie around, but having scored two goals in Belgium, Omonia will be confident of scoring a goal on home soil.
That would make progressing very difficult for Vanhaezebrouck's side, with potentially too much damage done in last week's first leg.