The result left Frankfurt fourth on 54 points with two games to play, ahead of fifth-placed Leverkusen on goal difference. Sixth-placed Borussia Moenchengladbach and Wolfsburg in seventh are a further two points adrift.
Frankfurt, looking bereft of energy after Thursday's 1-1 home draw with Chelsea in the first leg of their Europa League semi-final, were totally overrun in the opening period and lucky not to concede more than six in an astonishing first half.
Leverkusen's Lucas Alario struck twice and Kai Havertz, Julian Brandt and Charles Aranguiz also netted before Martin Hinteregger's own goal completed the scoring after 36 minutes, with Ante Rebic having pulled one back for Frankfurt.
Havertz opened the floodgates with a sweet left-foot shot from the edge of the penalty area in the second minute and Julian Brandt made it 2-0 in the 13th with a deft finish after a second assist by midfielder Aranguiz.
Rebic pulled one back for Frankfurt barely 60 seconds later with a heavily deflected shot but that was as good as it got for the visitors, with striker Alario heading in the home side's third in the 23rd minute.
The lively Aranguiz made it 4-1 when he blasted the ball into the roof of the net from close range after shaking off Makoto Hasebe and Alario grabbed his second with a tap-in after more good work by Kevin Volland.
Hinteregger's spectacular own-goal in the 36th added insult to injury as the centre back beat his own keeper Kevin Trapp with a diving header any striker would have been proud of, summing up Frankfurt's first-half nightmare.
With the game over as a contest, Leverkusen took their foot off the pedal after the break but still dominated with some crisp one-touch passing, as Havertz missed a pair of gilt-edged chances midway through the second half.
Frankfurt were reduced to almost walking pace in the closing stages and Havertz again came close when he fired inches wide from long range.
Earlier on Sunday, Schalke confirmed their place in the top flight with a 0-0 home stalemate against Augsburg while mid-table Fortuna Dusseldorf earned a 1-1 draw at Freiburg.
(Writing by Zoran Milosavljevic in Belgrade; Editing by Ken Ferris)
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