It's followed on Wednesday by another clash between the best in Spain and Germany when Barcelona host Bayern Munich.
All four teams have been European champions in the past 30 years but they have made mixed starts to this season's revamped and expanded format.
Dortmund have won both of their opening matches - 3-0 at Club Brugge and 7-1 at home to Celtic - to be the early leaders, and top scorers, in the 36-team table. Every side plays eight matches, four at home and four away.
Just like last season, when reaching the final against the odds before losing 2-0 at Wembley to Madrid, Dortmund have been more impressive in Europe than in the Bundesliga.
Madrid, meanwhile, surprisingly lost 1-0 at Lille last time, the defending champions' first defeat in the competition since the semi-finals in the 2022-23 season.
The second round of matches threw up several shocks, including Bayern losing 1-0 at Aston Villa to end their unbeaten run under new coach Vincent Kompany.
Now Bayern head to Barcelona and a reunion with Polish striker Robert Lewandowski, 36, who scored more than 200 goals for them.
Bayern will be looking for a seventh straight win in their head-to-head, a streak that includes a humiliating 8-2 defeat of Barca in the quarter-finals in 2020. Hansi Flick was in charge of Bayern that night and is now the coach of Barcelona.
Barcelona's Robert Lewandowski has continued to score freely since leaving Bayern Munich. (AP PHOTO)
Meanwhile, English champions Manchester City will set a record for consecutive games undefeated in the history of the competition - even stretching back before 1992 into the European Cup era - if they beat Sparta Prague at home on Wednesday.
Pep Guardiola's team is currently tied on 25 unbeaten matches with Alex Ferguson's Manchester United team from 2007-09.
City's last loss was a 3-1 defeat against Real Madrid in the second leg of the semi-finals in 2022, which cost them a place in the final.
Since then, they have won 17 matches and drawn eight, having won the competition in 2022-23 and been eliminated on penalties by Madrid in 2023-24.
Of the seven teams on a maximum six points, France's Brest are undoubtedly the most surprising.
This is the unheralded French team's European debut - in any competition - after an unexpected third-place finish in Ligue 1.
A 2-1 win over Austrian champion Sturm Graz was followed by a 4-0 thrashing of another Austrian team, Salzburg, but now they face German champion Bayer Leverkusen on Wednesday.
With each team playing eight games in the new league system, opening with back-to-back losses isn't the nightmare start it would have been in the old format when there were six matches per side in the group stage.
However, AC Milan, Leipzig, Girona, Salzburg, Sturm Graz, Slovan Bratislava, Young Boys and Red Star Belgrade will be desperate to get at least one point on the board in the third round of fixtures. Salzburg and Young Boys haven't even scored a goal.
Leipzig could easily be on zero points after three games, though, with Liverpool visiting on Wednesday - a match that has more intrigue since former Liverpool manager Jurgen Klopp was signed up as the head of global soccer at Red Bull, whose international network of clubs includes Leipzig.
25°C