With Mbappe starting as a substitute in Lille on Wednesday (Thursday AEST) after a minor hamstring injury, the decisive goal came from Canada striker Jonathan David 's penalty deep into first-half stoppage time. A video review ruled that midfielder Eduardo Camavinga handled the ball.
David scored a hat-trick last weekend and shot confidently past goalkeeper Andriy Lunin, who was replacing the injured Thibaut Courtois.
Mbappe came on in the 57th minute.
It was Madrid's first loss in the competition since a 4-0 hammering by Manchester City in the 2023 semi-final return leg.
Brazil teenager Endrick became the youngest Champions League starter for Madrid at 18 years, 73 days old. He surpassed the mark set by former Madrid great Raúl Gonzalez, who was 18 years, 78 days old when he faced Ajax in 1995.
Liverpool coach Arne Slot got his first taste of a European night at Anfield and saw his team beat Bologna 2-0, thanks to goals from midfielder Alexis Mac Allister and prolific forward Mohamed Salah.
Liverpool's Mohamed Salah scored his side's second goal in their 2-0 win over Bologna at Anfield. (AP PHOTO)
Substitute Jhon Duran scored a late winner to give Aston Villa another 1-0 win against Bayern Munich.
When the sides met in the 1982 European Cup final, Villa won 1-0 in a big upset. Prince William was born that year, and he was cheering in the Villa Park crowd when Duran pounced late on.
Coach Unai Emery sent the 20-year-old Duran on in the 70th minute and the Colombia forward, who has made a habit of scoring goals from the bench, did it again with a brilliant left-footed effort from about 25m to beat Bayern goalkeeper Manuel Neuer.
Juventus had goalkeeper Michele Di Gregorio sent off in the 59th minute for a handball yet still won 3-2 at Leipzig.
Slovenia forward Benjamin Sesko scored both goals for Leipzig, but Serbia's Dusan Vlahovic did the same for 10-man Juve before Francisco Conceicao netted in the 82nd minute.
Earlier, Atalanta and Feyenoord got their first wins in the competition's second round of matches.
Italian side Atalanta coasted to a 3-0 win over Ukraine's Shakhtar Donetsk, and Dutch club Feyenoord secured a gritty 3-2 win at tournament newcomers Girona.
Albanian Berat Djimsiti, Nigerian Ademola Lookman, and Italian Raoul Bellanova scored for Atalanta in the German city of Gelsenkirchen. It was officially a home game for Shakhtar, who are playing at German club Schalke's stadium because of the Russian invasion of Ukraine.
Girona led through centre-back David Lopez's close-range finish, but the visitors equalised with an own goal from Yangel Herrera, then took the lead thanks to Antoni Milambo's 31st-minute strike.
Donny van de Beek made it 2-2, but another own goal, this time from Ladislav Krejci, gave Feynoord - Slot's former club - victory in a match where both teams missed a penalty.
Kerem Akturkoglu, Angel Di Maria, Alexander Bah and Orkun Kokcu scored for Benfica in a 4-0 rout of Atletico Madrid, and Monaco netted a last-minute equaliser in a 2-2 draw at Dinamo Zagreb thanks to Denis Zakaria's penalty.
Sturm Graz lost 1-0 at home to Club Brugge, who won thanks to a curling strike from Christos Tzolis.
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