Victory for the reigning champions would make them the most successful visiting side at Old Trafford in the Premier League era.
It would be City's seventh victory at Man Utd's stadium, taking them ahead of Chelsea's six wins there.
Pep Guardiola could also become the first visiting manager to win three consecutive PL matches at Old Trafford.
By contrast his counterpart Ole Gunnar Solskjaer will be looking to avoid becoming the fourth successive Man Utd manager to suffer an opening derby defeat, after David Moyes, Louis van Gaal and Jose Mourinho.
Sergio Aguero can also claim a landmark. If he scores on Wednesday he will be the player with the most PL goals in the Manchester derby.
The City striker is level with ex-United forward Wayne Rooney, who scored eight goals in top-flight meetings between these sides.
If Aguero scores twice, it would take him level with Alan Shearer on 10 goals as the player to have scored most against the Red Devils in the Premier League.
Anyone who scores for City will also take the club level with the record goal tally of 156 in all competitions in one season, which was set in their title-twinning 2013/14 campaign.