Superb individual goals from English pair Mason Mount and Ben Chilwell gave Chelsea a 2-0 win away to Porto in their quarterfinal first leg in Seville.
Liverpool's Mohamed Salah and Sadio Mane were on target to snap a three-match losing run as their side stunned RB Leipzig 2-0 in another round of 16 first-leg tie.
Mbappe will miss Tuesday's Nations League international against Croatia.
Paris St Germain scored two late goals, including a stoppage-time winner from substitute Eric Choupo-Moting, to beat outsiders Atalanta 2-1.
Mbappe has been ruled out for three weeks after he suffered an ankle injury in Friday's French Cup final win over St Etienne.
Neymar struck early to secure a 1-0 win over 10-man St Etienne.
Wednesday marks the second anniversary of Les Bleus' triumph in the 2018 FIFA World Cup.
PSG pulled off an unlikely turnaround as Mbappe capitalised on a defensive mix-up to pull one back in the 81st minute before Pablo Sarabia, once of Real, drove into the top corner second later.
The runaway champions can clinch a domestic double when they take on Stade Rennais in the French Cup final next Saturday.
The 19-year-old Kylian Mbappe followed up a domestic treble with Paris St Germain with a string of impressive performances in France's World Cup-winning campaign.