The two sides drew 1-1 in the first leg in Germany last week, with Florian Wirtz salvaging a draw for the hosts eight minutes from the end of normal time.
Match preview
Having been on the cusp of relegation to the Belgian third tier only three seasons ago, Union SG's rapid rise under the ownership of Tony Bloom - who is also in control of high-flying Brighton & Hove Albion in the English Premier League - in recent years has been remarkable.
Les Unionistes became the first ever team to finish top of the regular season in the top flight of Belgian football directly after gaining promotion from the second tier, ultimately finishing in second place in the champions play-off system.
That is exactly where they find themselves once again this time around, with a fifth win in six league games against RFC Seraing at the weekend keeping them two points behind league leaders Genk ahead of the upcoming play-offs.
Karel Geraerts's side missed out on reaching the Champions League group stage after losing 3-2 on aggregate to Rangers in the third qualifying round, but they have used that to their advantage to reach the last eight of a European competition for the first time in 63 years.
After upsetting the odds to defeat their namesakes Union Berlin in the previous round, it would take a brave man to rule them out from dispatching another team in the shape of Leverkusen at Joseph Maren Stadium this week, especially having secured an impressive first leg result against Xabi Alonso's side.
However, Leverkusen will head to Belgium in excellent form themselves, having remained unbeaten in each of their last 11 matches after securing a 0-0 draw away to Wolfsburg on Sunday.
With RB Leipzig and Freiburg both winning above them in fourth and fifth positions respectively, dropping two points did no favours for Die Werkself's outside hopes of qualifying for the Champions League through a league position, with Alonso's side's hopes in that regard likely resting solely on winning the Europa League.
Leverkusen have only been beaten once in nine away trips in all competitions since returning to action from the World Cup in January, so despite being frustrated by their opponents at the Bay-Arena in last Thursday's first leg, they will have every confidence of completing the job at hand in Saint-Gilloise.
Clearly, though, they are likely to require a performance full of their usual attacking verve in order to do so, as Alonso - who only took over last October - aims to become the first Leverkusen manager to win a major trophy in 30 years.
Union SG Europa League form:
D
W
L
D
W
D
Union SG form (all competitions):
W
W
W
D
D
W
Bayer Leverkusen Europa League form:
L
W
W
W
D
Bayer Leverkusen form (all competitions):
W
W
W
W
D
D
Team News
Union SG will be forced to replace Siebe Van der Heyden after the defender received his third booking in this season's Europa League against Leverkusen last week, with Koki Machida likely to come into the hosts' back three.
Geraerts may also be tempted to throw Simon Adingra into his starting XI after surprisingly leaving the Brighton loanee on the bench for the entirety of last week's 1-1 draw, with Yorbe Vertessen potentially making way.
Leverkusen, meanwhile, will travel without Patrik Schick, Exequiel Palacios, Andrey Lunev and Charles Aranguiz due to injury, with Alonso likely to make a few changes from the side that played out a goalless draw in Wolfsburg.
Wirtz will almost certainly replace Sardar Azmoun in attack, with Amine Adli also expected to come into the visitors' starting XI at the expense of Adam Hlozek from the left flank.
Robert Andrich will move into his usual central midfield role after anchoring a back three on Sunday, with Jonathan Tah taking up that role after receiving a rare rest against Niko Kovac's side.
Union SG possible starting lineup:
Moris; Kandouss, Burgess, Machida; Niewkoop, Amani, Lynen, Teuma, Lapoussin; Adingra, Boniface
Bayer Leverkusen possible starting lineup:
Hradecky; Kossounou, Tah, Tapsoba; Frimpong, Andrich, Demirbay, Hincapie; Diaby, Wirtz, Adli
We say: Union SG 1-3 Bayer Leverkusen
Union SG have provided themselves with an excellent chance of continuing their fairytale adventure in the Europa League this season by drawing away from home in the first leg, but we can envisage it coming to an end on Thursday.
Leverkusen's form has been increasingly impressive under the tutelage of Alonso, and we expect them to seize the moment and keep their hopes of competing in the Champions League next campaign well and truly alive.