With Xabi Alonso forced to watch from the stands due to a yellow card suspension, Leverkusen turned on the style, winning with goals from Granit Xhaka, Patrik Schick, Jeremie Frimpong and penalties from Exequiel Palacios and Victor Boniface.
Alonso left midfield lynchpin Florian Wirtz, who turned 21 on Friday, out of the squad with Thursday's second Champions League semi-final against Roma in mind, but Leverkusen had no problems in attack.
Xhaka opened the scoring with a long-range effort, before Frankfurt equalised through Hugo Ekitike, who scored for the third game in succession. Schick headed Leverkusen back in front just before half-time and World Cup winner Palacios scored a third from the penalty spot on the 58-minute mark.
The floodgates opened in the final stages, with Frimpong scoring just five minutes after coming on and then Boniface converted a penalty for Leverkusen's first win in Frankfurt for six years.