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.
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.