It has been an excellent start for the two teams in their domestic leagues, with both managers being backed handsomely by their clubs over the summer.
Match preview
While there were some murmurings that Simeone could have left Atletico recently, the board have shown their ambition with multiple big-money signings this summer, and that has translated to points on the pitch.
Atletico are up in the top four with 11 points from their opening five matches, coming out of a tricky start unscathed, having already had to face Athletic Bilbao, Villarreal and Girona.
The hosts also bring superb home form on the continent into this clash, as they were the only club in last season's Champions League to maintain a 100% record on their own patch - five wins from five.
Facing another German team gives them the opportunity to extend a magnificent home record against sides from that nation too, as they are unbeaten this century in ties involving Bundesliga clubs - winning eight and drawing four - and an encounter with Bayer Leverkusen also awaits later on in the league phase.
Atletico will hope the new format in this competition can provide better fortunes given their multiple recent disappointments, as they have failed to get beyond the quarter-finals since their miraculous stretch of results between 2014 and 2017, which saw them reach two finals and a semi-final.
Upcoming opponents RB Leipzig inflicted one of those defeats on the Colchoneros, beating Atleti 2-1 in a one-legged COVID-era quarter-final in 2020 played in neutral Lisbon.
That remains Leipzig's best-ever performance in this competition, as their other five appearances have ended at either the group or last 16 stage.
Marco Rose's men are in for a difficult test in this new league phase, as they will face Italian giants Juventus and Inter Milan for the first time, while also hosting Liverpool at the Red Bull Arena.
Also on the horizon are Portuguese champions Sporting Lisbon, and Premier League top-four gatecrashers Aston Villa.
Leipzig will believe they can hold their own though, having made an unbeaten start to the season which involved a heroic comeback win over Bayer Leverkusen, becoming the first club to beat the German champions domestically in almost 18 months.
The international break came at the wrong time, as Leipzig struggled to take any momentum from coming back from 2-0 down to win 3-2 at the BayArena, as they drew 0-0 at home to Union Berlin on their return to action at the weekend.
RB have fallen to third as a result, but after winning their opening two games, and reaching the next round of the DFB-Pokal, it has been a largely pleasing start for manager Rose.
Atletico Madrid form (all competitions):
RB Leipzig form (all competitions):
Team News
The Atletico squad has been freshened up over the summer, with 24-year-old pair Julian Alvarez and Conor Gallagher both arriving from the Premier League.
That has brought their average age right down, considering it was 31 when they faced Borussia Dortmund in last season's quarter-final second leg - the club's highest-ever in this competition.
Both Gallagher and Alvarez scored at the weekend, the latter doing so off the bench, but Argentina's World Cup winner should come into the starting XI here, most likely replacing Alexander Sorloth.
On the injury front, Pablo Barrios (muscle) and full-back Reinildo (leg) are the only two current absentees for the hosts.
Leipzig are also without two players for this trip to Madrid, with Xaver Schlager recovering from an ACL injury, and Assan Ouedraogo sidelined for a few weeks with a less serious knee injury.
Captain Willi Orban has been serving a domestic suspension following a straight red card against Bochum, but he should come back into the side for this one.
Orban could line up alongside new boy Lutsharel Geertruida, who joined from Feyenoord late in the window and made his debut at the weekend, while Arthur Vermeeren could face his parent club after arriving on loan from Atletico over the summer.
Atletico Madrid possible starting lineup:
Oblak; Le Normand, Gimenez, Azpilicueta; Marcos Llorente, De Paul, Koke, Gallagher, Lino; Alvarez, Griezmann
RB Leipzig possible starting lineup:
Gulacsi; Geertruida, Orban, Lukeba; Henrichs, Haidara, Kampl, Raum; Sesko, Simons, Openda
We say: Atletico Madrid 3-1 RB Leipzig
Atletico have not lost at home to a German club in the 21st century, and enter the fixture high on confidence after another big win at the weekend over Valencia.