After a low-key opening, this tie exploded into life on the 19-minute mark when Freiburg hit the front.
Vincenzo Grifo’s free-kick from the left was met by a pinpoint glancing header by Matthias Ginter that went in via the far post, with the centre-back’s third goal in six matches levelling the tie on aggregate.
Undeterred, Genk ought to have hit back almost immediately when Joris Kayembe overlapped down the left and picked out Aaron Bibout with a brilliant cross, but Noah Atubolu was equal to his shot, preserving the hosts’ lead on the night with a fantastic save.
That stop looked even more crucial when Julian Schuster’s men edged ahead on aggregate before the half-hour mark, with Ginter heavily involved once more.
Yuito Suzuki’s effort deflected fortuitously into Ginter’s path in the box, and he headed across goal for Igor Matanovic to bundle home at the far post for his ninth goal of the campaign.
Genk looked shellshocked having conceded twice in quick succession, but recovered and soon started to apply pressure of their own.
They restored aggregate parity before the break when Konstantinos Karetsas’ shot hit the post and rebounded across the face of goal and back to the Greek, who squared for Smets to fire past Atubolu.
Ken Nkuba spurned a big chance for Genk to go back ahead overall before half-time too, firing over from Bibout’s cutback to leave the tie finely poised ahead of the second half.
Momentum looked to be with the visitors at the interval, but the pendulum swung Freiburg’s way upon the restart.
A self-inflicted wound from Genk saw their goalscorer Smets play a wayward pass across his own box that Grifo pounced on to fire home his 106th goal for Freiburg, moving him clear as the club’s outright all-time top scorer.
Then, just four minutes later, Suzuki started and finished a blistering counter-attack, slotting into the bottom corner after being played through by Johan Manzambi, handing them what looked like an unassailable two-goal aggregate lead.
Genk never looked like recovering from that double blow, and their fate was confirmed in the 79th minute when Maximilian Eggestein slammed home from the edge of the area.
An emphatic attacking display may have come as a surprise to the home support, given that Freiburg had failed to score in three of their prior four matches, but they can now look forward to a quarter-final tie against Celta Vigo.
Genk miss out on their first last-eight appearance since 2016/17, with this miserable result stretching their winless run in away games against German opponents to five matches.
Flashscore Man of the Match: Vincenzo Grifo (Freiburg)
