Leverkusen have now lost five home matches in a row in all competitions and not won in nine, as Sami Hyypia's fourth-placed side continue to slide towards the UEFA Europa League places.
The hosts could count themselves unlucky, as Omer Toprak had a late goal - that would have given them a 3-2 lead - wrongly disallowed, but their defensive frailties were again showed up.
The reverse fixture at Hoffenheim was marred by Stefan Kiessling's 'ghost goal', in which the forward's header crept in through a hole in the corner of the net and was controversially allowed to stand.
And Kiessling again came back to haunt Hoffenheim, cancelling out Sejad Salihovic's early penalty with a 39th-minute goal.
Kevin Volland responded immediately for Markus Gisdol's side as they took a 2-1 lead into the break.
Simon Rolfes levelled proceedings again, though, finishing a delightful team move with a curled finish nine minutes into the second half.
Leverkusen should have been in front only for Toprak - who followed up his header, which hit the post, and tapped in - to have his goal chalked off, when it was Kiessling, who did not interfere with play, who appeared to be offside.
Anthony Modeste then won it at the death for Hoffenheim, sweeping home Fabian Johnson's cross in the 89th minute, before he checked the net for holes in ironic celebration.
Leverkusen still sit fourth, but are now seven points behind the second-placed Borussia Dortmund.
Sunday's other match saw Eintracht Frankfurt win 5-2 at relegation-threatened Nuremburg.
Just one of the seven goals was scored in the first half, which also saw Ondrej Petrak substituted for the losers after suffering suspected concussion and a broken nose.
Tranquillo Barnetta put Frankfurt ahead in the 21st minute, converting Stefan Aigner's drilled cross.
Aigner also set up the second, scored by Joselu in the 49th minute, and when Alexander Madlung quickly followed that with Frankfurt's third, the match looked over.
Nuremburg hit back though, with Josip Drmic's 64th-minute goal added to by an effort from Crystal Palace loanee Jose Campana.
That set up a thrilling final 20 minutes, but a red card to Nuremburg defender Javier Pinola would swing the match back in Frankfurt's favour.
Joselu restored Frankfurt's two-goal buffer with two minutes to play and Vaclav Kadlec wrapped up the win in stoppage time as the winners moved six points clear of the relegation zone.
