Union SG are aiming to reach the last four of a European competition for the first time since losing to Birmingham City in the semi-final of the Inter-Cities Fairs Cup in 1959-60, while Leverkusen have not progressed beyond a quarter-final since finishing as runners-up in the 2001-02 Champions League final.
Match preview
Indeed, after enduring a disastrous start to their domestic campaign and belatedly crashing out of the Champions League at the group stage, Leverkusen have recovered to build a highly respectable season under the tutelage of Xabi Alonso.
The Spaniard, who replaced Gerardo Seoane in Leverkusen's dugout last October to seal his first top-flight managerial role, quickly guided Die Werkself away from their growing relegation fears, with their 3-1 win over Eintracht Frankfurt at the weekend seeing them leapfrog their opponents into sixth position in the Bundesliga.
Goals from Amine Adli, Moussa Diaby and Sardar Azmoun helped their side record an eighth win in nine matches in all competitions, which is a record that will contribute to them heading into Thursday's tie against Union SG as heavy favourites to progress to the last four of the Europa League.
With fourth-placed RB Leipzig only five points ahead of Leverkusen with seven league games remaining and the winners of the Europa League automatically qualifying for the Champions League group stage, Alonso will have real belief that he will be involved in a competition which he won twice as a player once again next season.
However, the former Bayern Munich midfielder will be guarding his players against any degree of complacency, with their forthcoming opponents' individual abilities clearly outweighing their club's historical pedigree on the grand stage.
For Union SG, their surprising run to the quarter-finals of Europe's secondary competition this campaign represents uncharted waters for the club, who were competing in the second tier of Belgian football only two seasons ago.
Owned by Tony Bloom, who has also helped oversee Brighton & Hove Albion's similar rise up the English footballing pyramid in recent years, Les Unionistes comfortably conquered their namesakes Union Berlin 6-3 on aggregate in the previous round to set up another tie against German opposition.
Head coach Karel Geraerts will be acutely aware that Leverkusen, in their current guise under Alonso, potentially represent a step-up in class despite them being eight points and three places behind Union Berlin in the Bundesliga table ahead of the first leg clash.
Having chased Genk down to move within two points of the Belgian First Division leaders at the top of the table with a superb run of form in recent weeks, the 41-year-old will be quietly confident of causing yet another upset during this remarkable period of the club's history.
That said, they will need to defend much better than they did when conceding three goals in Berlin to Urs Fischer's side, with the likes of Florian Wirtz and Diaby capable of tearing any opponents apart on their day.
Bayer Leverkusen Europa League form:
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W
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Bayer Leverkusen form (all competitions):
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Union SG Europa League form:
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D
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Union SG form (all competitions):
D
W
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D
Team News
Leverkusen appear set to be without Kerem Demirbay, Nadiem Amiri, Patrik Schick, Andrey Lunev and Charles Aranguiz due to injury, while Alonso will also be sweating over the fitness of Piero Hincapie (hip) and Adam Hlozek (illness).
Hincapie was withdrawn late on during Leverkusen's 3-1 win against Frankfurt at the weekend, while Hlozek was not involved at all. Should the former miss out as would seem likely given the short turnaround between fixtures, Mitchel Bakker is likely to be preferred to Daley Sinkgraven at left wing-back.
Azmoun could replace Adli in attack, meanwhile, with Jeremie Frimpong continuing to provide the bulk of the hosts' width from his penetrating role down the right flank.
Union SG, on the other hand, may travel to Germany with a fully fit squad at their disposal, meaning Geraerts is free to select what he considers to be his strongest starting XI.
In the previous round, the 20-time Belgian international utilised a 3-5-2 formation, so it seems likely that he will continue with this in order to roughly match up against Alonso's preferred system during his time at Leverkusen.
That would mean Simon Adingra and Victor Boniface forming a dangerous pair in attack, as they aim to hit their more adventurous opponents in transition as quickly and often as possible.
Bayer Leverkusen possible starting lineup:
Hradecky; Kossounou, Tah, Tapsoba; Frimpong, Andrich, Palacios, Bakker; Wirtz; Azmoun, Diaby
Union SG possible starting lineup:
Moris; Kandouss, Burgess, Van Der Heyden; Nieuwkoop, Amani, Lynen, Teuma, Lapoussin; Adingra, Boniface
We say: Bayer Leverkusen 3-1 Union SG
While we expect Union SG to pose Leverkusen with plenty of headaches across the course of this encounter, the Germans have become a consistent outfit during Alonso's reign, and we believe they will head to Saint-Gilloise with a healthy lead to protect in the return leg next week.