Bayer Leverkusen's 35-game unbeaten Bundesliga run came to an end as RB Leipzig recovered from 2-0 down to take all three points against the reigning champions.
Lois Openda scored Leipzig's winner late in the second half, sending a powerful shot past goalkeeper Matej Kovar from outside the penalty area.
Jeremie Frimpong had given the hosts the lead in the first half after skipping past defender El Chadaille Bitshiabu and beating goalkeeper Peter Gulacsi at his near post.
Xabi Alonso’s team doubled their advantage six minutes later when Alex Grimaldo turned in Florian Wirtz's pass from point-blank range, but former Leverkusen midfielder Kevin Kampl reduced the arrears with a header from Benjamin Henrichs' cross in first-half stoppage time.
Openda converted Benjamin Sesko's pass from a tight angle to bring the teams level 12 minutes into the second half, before firing home the winner with 10 minutes remaining.
Leipzig boss Marco Rose was sent off midway through the first half after remonstrating with referee Matthias Jollenbeck following Jonathan Tah's challenge on Openda.
Leverkusen, whose only defeat last season came in the Europa League final loss to Atalanta, had not been beaten in Germany's top flight since a 3-0 defeat at Bochum on the final day of the 2022-23 campaign - 462 days ago.
This outcome extends Leipzig's own unbeaten league run to 13 matches, stretching back to last term.
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