All games from this point on are hosted in Portugal and just a 90-minute affair, so there’s no margin for error.
Leipzig finished third in the Bundesliga and knocked out Tottenham in the last round in Europe.
Atleti similarly ended third in LaLiga, while they put Liverpool to the sword in the last 16.
Here’s everything you need to know about the match.
When is it and what time is kick-off?
The match will begin at 8pm BST on Thursday 13 August at the Estadio Jose Alvalade.
How can I watch it online and on TV?
The game will be broadcast live on BT Sport 1 and BT Sport Extra 1, as well as BT Sport Ultimate.
Subscribers can also stream the match on the BT Sport website and app.
RB Leipzig will be without Timo Werner, of course, after the striker completed his move to Chelsea. Atletico are without Thomas Partey in midfield, while centre-back Felipe is not fully match fit.
RB Leipzig: Gulacsi, Klostermann, Upamecano, Halstenberg, Sabitzer, Laimer, Kampl, Angelino, Nkunku, Poulsen, Dani Olmo.
Atletico Madrid: Oblak, Trippier, Savic, Gimenez, Renan Lodi, Koke, Hector Herrera, Saul, Carrasco, Marcos Llorente, Costa.
Leipzig — 12/5
Draw — 23/10
Atletico — 11/8