Lyon coped much better with the wet conditions and Nabil Fekir put the home side ahead after 19 minutes when he netted from close in after a thunderous strike from Ferland Mendy came back off the woodwork.
Tanguy Ndombele made it two eight minutes later when he capped a nice passing move by stroking the ball home from Mendy's cut-back.
Any hopes of a comeback looked remote when Kasim Adams Nuhu was sent off for the visitors six minutes into the second half but the decision appeared to energise the Germans and Andrej Kramaric got a goal back 14 minutes later.
Lyon, who had the bulk of the goal-scoring opportunities, had reason to rue their missed chances when in the second minute of injury time Czech defender Pavel Kaderabek blasted home from close range to give Hoffenheim a share of the points.
The goal was only Kaderabek's second in 34 European appearances but it helped the German side move off the bottom of Group F and on to three points, one ahead of Shakhtar Donetsk, who lost 6-0 to Manchester City in Wednesday's other game.
City lead the group with nine points, three clear of Lyon.
"When you're two-nil down at half-time away from home, you have to choose to go out and go all-in," said Hoffenheim defender Ermin Bicakcic. "We could have scored a late winner even after the equaliser."
Fekir, who scored Lyon's first goal, said: "Our problem at the moment is that when we concede we’re not calm after it.
"It wasn’t a good evening. It’s got to the stage where we’re repeating ourselves but we’re trying to correct things.
"After their red card our intensity levels dropped a bit and some of the tempo went. We gave them more confidence and they managed to get back on terms. It’s sad for us.”
(Reporting by Andrew Downie,; Editing by Neville Dalton)
