Lars Bender put Leverkusen in front and Daniel Ramos Carvajal made it two before the break.
Hoffenheim responded in the second half as Fabian Johnson brought them back into the game, but they were unable to find an equaliser as their worst-ever start to a Bundesliga season continued.
Hoffenheim coach Markus Babbel is beginning to get used to a relegation battle as opposed to a push for Europe, and that sentiment strengthened after 15 minutes.
Bender tucked the ball in after Hoffenheim failed to clear their lines from a free-kick and Simon Rolfes had both the vision and the composure to set up his team-mate and resist the temptation to shoot himself.
Koen Casteels, in the Hoffenheim goal for the injured Tim Wiese, bravely intervened to deny Andre Schurrle the chance to make it two in the 22nd minute as the Hoffenheim defence was all at sea.
Only Firmino was able to provide any flashes of danger at the other end, but even his tricky dribbles ended up down a dark alley of Leverkusen defenders.
Carvajal doubled Leverkusen's lead in the 38th minute just as Hoffenheim were beginning to get a foothold in the game.
He played a neat one-two with Schurrle before skipping past Casteels and dispatching the ball into the unguarded net just before losing his balance.
Exactly what Babbel told his team at half time will remain a secret, but there was no hiding the reaction it caused.
They were rewarded on the hour mark when Johnson brought them back into the game, his shot taking a telling deflection off Kevin Volland on its way past Bernd Leno.
Sven Schipplock missed a hat-trick of chances late on as Hoffenheim failed to find an equaliser.