The hosts nearly took a surprise lead when Marius Bulter squared the ball to Haris Tabakovic but the Bosnian sliced the ball wide of the far post with only the goalkeeper to beat.
Adam Hlozek was next to test the visitors' backline following a mazy run, but a Leipzig defender was able to block the shot, as Hoffenheim continued to control the early proceedings.
Leipzig got through the early pressure and were quick to try and establish control, as they grabbed the lead through the run of Willi Orban, who slid into the six-yard box to smash past Oliver Baumann.
That lead lasted for only minutes, as the hosts found the equaliser through Hlozek, whose quick footwork got him past a defender in the box before he smashed the ball into the top right of the visitors' goal.
Hoffenheim had barely finished celebrating when Lois Openda cut the ball back to Antonio Nusa, who confidently curled a spectacular effort over Baumann.
Neither side were ready to yield, as they both traded chances throughout the remainder of the first half.
Hlozek continued to be the hosts’ offensive spark after the restart, as he got their first shot of the second half with another run that had Leipzig defenders scrambling to prevent his shot from causing Peter Gulacsi any trouble.
That was just a warning, as the hosts were level moments later, as Tom Bischof curled a freekick from the edge of the box into the left side of the visitors' goal, to register his first senior goal.
As the half progressed, Leipzig finally started to take command of the game, as they started to apply the pressure on the host’s goal.
That pressure would finally give way when Nusa swung another fantastic cross from the left wing, as the pressure from Openda in the box saw Stanley Nsoki poke the ball into his own net to restore their lead.
Just as it seemed like the game had gotten away from the hosts they found their third equaliser of the day, as Jacob Bruun Larsen found Hlozek in the box, with the attacker able to find the bottom right of the goal in a congested box.
The hosts weren’t done yet, as Anton Stach played a perfectly weighted cross into the middle of the box, with Bruun Larsen rising highest to head past Gulacsi to give them the lead for the first time in the game.
The win sees Hoffenheim open a four-point gap on St. Pauli in the relegation playoff spot, as well as ending their six-match winless run against their opponents.
Meanwhile, Leipzig will regret their inability to build on any of their leads, as they lose even more ground on Bayern Munich in first place.
Flashscore Man of the Match: Tom Bischof (Hoffenheim)