Aymeric Laporte, Benjamin Mendy, Fernandinho, Gabriel Jesus and Sergio Aguero were dropped to the City bench, while Dortmund featured Erling Braut Haaland and Marco Reus as their mainstay in attack as former City player Jadon Sancho missed out through injury.
The Citizens broke the deadlock two minutes before the midway stage when Kevin De Bruyne applied a first-time finish from a low ball on the right-side by Riyad Mahrez.
Matters worsened for Dortmund right on 30 minutes when a foul by Emre Can on Rodri earned City a penalty but following a review from the Video Assistant Referee (VAR), it was overruled.
The match began to open up in the last six minutes of the first half as Jude Bellingham pounced on an error by goalkeeper Ederson Moraes to go clear, but the whistle went up.
Haaland missed a golden chance to draw the visitors level two minutes in the second half from a through ball by Mahmoud Dahoud, but Ederson thwarted the move quite effectively.
The Citizens introduced a substitution from the bench towards the last 30 minutes in Jesus, who replaced Bernardo Silva.
A second goal for the Premier League leaders loomed midway in the second half from a low shot in the centre of the area by Phil Foden following a ball from the right, but it was cleared off the line.
Foden came close again with 15 minutes to go through a low rasping shot from outside the area, but goalkeeper Marwin Hitz parried back into play with the follow-up cleared away.
It is a missed chance that would haunt the Citizens as Reus combined with Haaland six minutes before time to fire the equaliser from inside the area.
City though restored the lead in added time with a first-time finish from close-range by Foden following a cutback by Ilkay Gundogan, as the match concluded with the return-leg next week.
