Hoffenheim are in serious relegation danger at the bottom of the table.
Stefan Kiessling and Andre Schurrle scored two goals each for Leverkusen with Stefan Reinartz adding a fifth.
Simon Rolfes saw his penalty saved after Eugen Polanski was shown a red card for the visitors, who remain six points adrift of safety with just four games of the season remaining.
Kiessling volleyed Leverkusen in front in the 16th minute, sending the ball unstoppably into the top left-hand corner from Schurrle's pull-back.
The Germany forward caused problems again five minutes area with only a foul by Polanski preventing him from making it two.
The Hoffenheim midfielder saw red with Rolfes stepping up to take the consequent penalty, but Koen Casteels guessed right to deny him.
It was only a brief respite for the visitors, who went two behind soon after when Schurrle finished well for his 10th goal of the season, impressing Chelsea, who are reportedly close to signing him for next season.
It was a similar story in the second half with Kiessling and Schurrle both on target again.
Kiessling's 21st goal of the season came with a header from Daniel Carvajal's cross in the 65th minute and Schurrle then converted Kadlec's pass to make it four less than five minutes later.
Hoffenheim simply could not compete and Casteels had to fish the ball out of the back of his goal again in the 79th minute.
He initially denied Arkadiusz Milik, who then hit the post before the ball fell for Reinartz to make it five and give Leverkusen a seven-point advantage over fourth-place Schalke.