Looking to bounce back from their opening day defeat against FC Koln, the home side had Dortmund completely pinned back throughout the first half, but it took some time to find a way past Gregor Kobel.
Adam Hlozek was the first to threaten as he found space just outside the box, but his fizzing half-volley sailed wide of the near post. The best chance of the game came just before the half-hour mark, with Tim Lemperle undoing the visiting defence with a clever backheel.
That left Adam Daghim free on the left, and his angled drive was headed for the bottom corner, only for Kobel to tip the ball wide with an excellent save.
With his side already struggling, Niko Kovac was forced into a reshuffle after an injury to Filippo Mane. Hoffenheim continued to push and got their reward just before half time when Leon Avdullahu scored with a stunning curled effort from 25 yards.
The pattern continued after the break, with the home side doubling their lead on 54 minutes. Tim Lemperle showed great tenacity to dispossess Joane Gadou in his own half before running through on goal, and his shot took a big deflection to loop over Kobel and into the net.
At that point, it looked like game over; however, Dortmund suddenly burst into life on the hour mark with a quick-fire double.
Waldemar Anton sparked the comeback by winning possession high up the field before unselfishly tapping the ball into the path of Serhou Guirassy, who made no mistake with a classy dinked finish.
Guirassy then turned provider, playing in substitute Fabio Silva for a fantastic angled finish to stun the home crowd.
That set up a pulsating finish with both sides pushing to find a dramatic winner, and the visitors completed the stunning turnaround with three minutes to go.
A surging run from Ethan Nwaneri ended with the deadline-day signing playing the ball across goal, and Albian Hajdari could only turn it into his own net.
Letting a two-goal lead slip marks a frustrating start to the season for Hoffenheim, with back-to-back 3-2 defeats despite leading in both games, while Dortmund sit joint top with two wins from two.
Flashscore Man of the Match: Waldemar Anton (Borussia Dortmund)