Pep Guardiola's side have beaten Real Madrid at the Bernabeu, won a third successive EFL Cup trophy and progressed through to the quarter-finals of the FA Cup since they were last in Premier League action.
A difficult test awaits them upon their return, though, with Champions League-chasing United having already beaten them twice this season.
Here, Sports Mole looks at how Guardiola could line his side up for the contest.
Man City's preparations for the short trip to Old Trafford have been dealt a blow by an injury to arguably their most important player, with Kevin De Bruyne missing the midweek FA Cup win over Sheffield Wednesday.
Guardiola revealed in his pre-match press conference that the Belgian was "getting better", though, and he is set for a late fitness test as he battles to recover in time.
The experienced David Silva and the youth of Phil Foden - man of the match in last weekend's EFL Cup final - are waiting in the wings should De Bruyne fall short, with Ilkay Gundogan looking most likely to start in the third midfield spot alongside Rodri.
One of Guardiola's most intriguing decisions will be who to start up front, with Gabriel Jesus having featured regularly recently and scored the winner in their most recent league outing.
However, Sergio Aguero's record in this fixture could earn him the nod; the Argentine is just one goal short of equalling the Man City record for derby goals and two behind Wayne Rooney's all-time leading tally of 11.
Aguero surpassed another Rooney record with his winner against Sheffield Wednesday in midweek, with that strike taking him to 254 goals in 367 appearances for Man City - one more than United's leading scorer managed in 559 outings for the Red Devils.
The Argentine also now has 23 goals across all competitions this season - more than any other Premier League player - so it would be a surprise if he was to miss out as he did at the Bernabeu.
Raheem Sterling's travails against United have been almost a polar opposite of Aguero's, with the winger still yet to find the back of the net in any of his 19 previous meetings with the Red Devils during his time at Liverpool and Man City - by far his worst record against any opponent.
Nonetheless, the England international's absence from the starting lineup at Hillsborough suggests that he will start this match, while the likes of Ederson, Kyle Walker and Fernandinho are also expected to come back into the side.