Nathan Tella in the 26th minute, Nordi Mukiele in the 29th and Patrik Schick in the 33rd set Leverkusen on course in Saturday's rout.
Frankfurt were back in the game with a goal from Hugo Ekitike in the 37th, but the title holders clinched matters from Aleix Garcia in the 62nd.
"We played a very good first half, pressed well, won many balls and scored on our chances," Leverkusen playmaker Granit Xhaka told Sky TV.
Frankfurt goalkeeper Kevin Trapp conceded: "We faced an absolute top team. Leverkusen were a notch or two better."
It pushed Leverkusen back to within eight points of leaders Bayern, who had won 3-1 at VfB Stuttgart on Friday.
Frankfurt remain third despite a second big defeat a week after a 4-0 humbling in Munich.
But they have surprise team Mainz breathing down their necks one point behind in fourth after a 2-1 comeback victory at RB Leipzig.
Borussia Dortmund got successive victories for the first time in the season, with a 2-0 win at St Pauli to keep their top-four hopes alive despite trailing Mainz by six points in 10th.
Leverkusen visit Bayern on Wednesday for the first of their European meetings, but that did not distract them in Frankfurt where coach Xabi Alonso had lost 5-1 in his first outing in 2022 while winning with the same scoreline there last season.
Tella opened the scoring into the bottom corner after wrong-footing a defender off Xhaka's superb pass, and Mukiele poked the second three minutes later in a goalmouth scramble.
Schick drilled home the third for a season tally of 16 off Alejandro Grimaldo's low cross against a stunned Frankfurt side.
The hosts pulled one back in the 37th when Mukiele chased down Ekitike but then played a poor backpass to goalkeeper Lukas Hradecky which Ekitike intercepted to score.
Frankfurt fought on after the break but it was all over for them when Garcia volleyed home from a distance in the 62nd as Alonso recorded a league-record extending 29th unbeaten league match in a row away from home.
Looking ahead to Wednesday, Xhaka said: "We are stable enough to annoy Bayern. We are still in three competitions."
Elsewhere, Werder Bremen's recent misery continued with a 2-1 home defeat against Wolfsburg from Patrick Wimmer's brace, and Robin Hack also scored twice as Borussia Monchengladbach won 3-0 at second-last Heidenheim.
Hoffenheim got a vital 1-0 victory at Bochum in the lowlands from Tom Bischof as all seven games so far this weekend were won by the visiting team.
