Kevin-Prince Boateng and Joel Matip got Schalke off to a flying start, but Anthony Modeste hauled Hoffenheim back into the game.
Marco Hoger restored Schalke's two-goal advantage before half-time, but a Roberto Firmino penalty and a David Abraham free-kick earned Hoffenheim a share of the spoils.
With Adam Szalai left on the be bench, Boateng took his place as Schalke striker, and he only needed three minutes to show how much he felt at home in his new role, netting his second goal of the season to put the visitors ahead.
Max Meyer, making his starting debut in a Bundesliga match, pulled the ball back from the goal line to the Ghanaian, who left Koen Casteels little chance with a powerful drive into the top corner.
Meyer and Boateng combined again, this time with the former getting in a shot, which was deflected wide.
Schalke doubled their advantage in the 13th minute when Jefferson Farfan's free-kick from the left was headed in from the edge of the six-yard box by Matip.
Hoffenheim had hardly threatened until Timo Hildebrand and Benedikt Howedes got in each other's way before the latter made a poor clearance which Andreas Beck squared for Modeste to score his eighth goal in nine games.
With an average of over five goals per game for Hoffenheim so far this season, it was hardly surprising that another goal came before the break with Hoger stretching Schalke's lead.
He received the ball from a Dennis Aogo throw-in and ventured straight towards goal, leaving four Hoffenheim defenders standing before threading his shot through the legs of Casteels.
The home team reduced the arrears once again, keeping up the five-goal average in their games this season from the penalty spot with Firmino firing past Timo Hildebrand after Aogo brought Kevin Volland down inside the area.
Hoffenheim were right back in the game, and they levelled matters after an hour when Abraham curled a direct free-kick over the wall and in with Hildebrand getting his fingertips to it, but not managing to keep the ball out.