Christopher Nkunku put Leipzig in front in the 29th minute and Jesse Marsch's side missed numerous chances to build on their lead before they were punished by a Marco Reus equaliser early in the second half.
But Yusuf Poulsen restored Leipzig's advantage in the 68th, sliding to the floor to send a cross from Nkunku inside the near post and clinch the first win for his side over Dortmund in over four years.
The result left second-placed Dortmund on 24 points after 11 games, four behind Bundesliga leaders Bayern Munich who beat Freiburg 2-1 at home earlier on Saturday. Leipzig climbed up to fifth on 18 points.
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