Despite heading into the first match as favourites against Lazio, the Bundesliga side lost 3-1 in Rome.
Following that defeat, Lucien Favre switched formation to a 4-2-3-1 in the weekend's fixture against Schalke, and it worked as Dortmund kept a clean sheet and won 3-0.
With Emre Can currently missing due to coronavirus isolation, it will probably be two centre-backs against Zenit, with the returning Manuel Akanji having impressed against Schalke on Saturday. He'll partner Mats Hummels.
Jude Bellingham started the game against Lazio before being dropped for domestic action, and due to the increased level of performance from Dortmund it is likely that Thomas Delaney or Mahmoud Dahoud will partner Axel Witsel in central midfield.
The Belgian was left out of the starting XI at the weekend but will probably be reinstated for Champions League duty.