The highly-rated Kai Havertz started up top with Lucas Alario also featuring for Bayer, who endured a tough loss to Bayern Munich last week.
Schalke were the ones starting brightly with a powerful strike from Weston McKennie unsettling Werkself whilst Ahmed Kutucu failed to latch onto the rebound.
Die Werkself got up and running after coming away unscaved and found Alario on the end of a cross which failed to get the better of a stubborn defence following the midway stage.
Daniel Caligiuri gave the travelling side a big scare with a rasping shot off Alessandro Schopf's ball with 27 minutes on the clock, but Lukas Hradecky got down to make a save.
Havertz was given his first sight on goal in the final minute to halftime, but failed to head home Nadiem Amiri's well-weighted delivery.
Schalke were ahead seven minutes after the break, as Caligiuri fired home from the penalty spot following a hand ball in the area with Edmond Tapsoba the guilty party.
Alario looked to bring the visitors level a little later on, but had Schalke shot-stopper Alexander Nubel equal to the task following a right-footed shot.
Leverkusen opted for the bench in the last 20 minutes and introduced Kevin Volland and Daley Sinkgraven for Havertz and Amiri respectively.
The invention from Peter Bosz paid dividends with nine minutes remaining as Juan Miranda found his own net after attempting a clearance.
Leverkusen went all out for the winner towards full-time, but Alario amongst others fired blanks as it ended all square.