Derdiyok left Bayer last summer, but will now play for them until the end of the current season, to the delight of director of football Rudi Voller.
"The signing of Eren Derdiyok means we have found a powerful, internationally experienced striker," he told Bundesliga.com.
"Eren knows how things work here in Leverkusen and he played some great games during his time here, but he was not always able to deliver on his full potential. We're now giving him that chance. We're convinced that he'll take it."
The player, too, was pleased to be back and is looking forward to playing in the Champions League.
"Leverkusen are the right club for me to get my career back on track," he said. "I was always happy here and I know most of the team, and we're playing in the Champions League.
"This is a great challenge and I'll give it all I've got so that we'll be successful this year."
Derdiyok scored 24 goals in the three seasons he spent at Bayer previously.