Louis van Gaal will be desperate for victory to prove the critics wrong, while Manuel Pellegrini will hope his side can maintain the form that saw them score 11 goals in their last two league games.
The Citizens go into the derby without David Silva and Sergio Aguero, who picked up injuries while on international duty.
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Meanwhile, Ashley Young is a doubt for United and Luke Shaw remains sidelined. With injuries in mind and the form of the players considered, who would make a combined Manchester XI?
Here's a starting 11 of players fit for this weekend's encounter:
GK: DAVID DE GEA
The Manchester clubs have two of the best goalkeepers in the world in the shape of Joe Hart and David de Gea.
The City 'keeper responded well to being dropped last season and he is now performing better than ever, but it's difficult to look past De Gea. United fans were resigned to losing him this summer, but the Spaniard stayed and has quickly quelled any fears that his head might not be in the right place with a series of superb displays.
The 24-year-old is seriously challenging Bayern Munich's Manuel Neuer for the title of world's best goalkeeper.
RB: MATTEO DARMIAN
The Italian made an excellent start to the season but has experienced a rough patch over the last few weeks, most notably against Alexis Sanchez during United's collapse at the Emirates two weeks ago.
Thankfully for United, he was more like his usual self in the victory over Everton, and given that Pablo Zabaleta hasn't played a lot of football this season, Darmian would certainly make a Manchester XI.
CB: VINCENT KOMPANY
The Belgian has been at the centre of a club vs country row over the last few weeks and the City captain hasn't featured since September 12 due to injury.
However, Kompany was rested for City's clash with Sevilla, which suggests he's in line for a start at Old Trafford. The centre-half was in great form prior to his injury and the fact City have failed to keep a clean sheet in his absence shows his importance to the team.
The 29-year-old would be one of the first names on the team sheet in a Manchester XI.
CB: CHRIS SMALLING
This looks to be Smalling's breakthrough season - something United fans have had to wait a long time for. The Englishman has been one Van Gaal's best players this season after putting in a number of commanding performances at the back.
The 25-year-old is finally delivering on his potential after a difficult start to life at the club. Strong, authoritative and increasingly composed on the ball, Smalling would be a fantastic partner for Kompany in the heart of the defence.
LB: ALEKSANDAR KOLAROV
Shaw's season-ending injury makes this a toss up between Kolarov and Marcos Rojo.
The Argentine may have impressed against Everton last week, but he's no match for the experienced Serbian, who looks set to return from injury this weekend. He may not be blessed with pace, but Kolarov offers a genuine threat when going forward with his wonderful left foot.
RM: JUAN MATA
The Spanish international is still not playing in his favoured position, but he's made an excellent start to the season nonetheless.
The 27-year-old was subbed at half-time against Everton for tactical reasons, but he's still very much a key player for Van Gaal. The midfielder has three goals and three assists to his name already this season.
If Silva was available then Mata's place in a Manchester XI would be less assured, but given his compatriot is ruled out, he comfortably makes the cut.
CDM: YAYA TOURE
Love him or hate him, you can't deny the qualities that Toure brings to City's midfield.
The Ivorian was arguably the most important player in City's two title triumphs and he will hope he can help the side to a third this season.
And while he might continue to bemoan the lack of respect that he gets in England, when he lets his football do the talking there can be no disputing his importance to the team. At his best, he is virtually the complete midfielder.
CDM: MORGAN SCHNEIDERLIN
The Frenchman scored his first United goal in the 3-0 demolition of Everton and will surely start Sunday's Derby.
His summer arrival from Southampton has been quietly effective so far and brought solidity in front of United's rearguard.
He's not going to offer the same quality in attack as Toure, nor the creativity of Bastian Schweinsteiger, but Schneiderlin's all-action game would bring balance.
LM: KEVIN DE BRUYNE
The easiest pick considering his current form. Needless to say, many were sceptical when City invested over £50 million in De Bruyne, but the midfielder has made an instant impact.
The Belgian has scored in three of his five league appearances and provided three assists for his team-mates. The 24-year-old looks to be one of the signings of the summer and will soften the blow of losing both Aguero and Silva to injury.
CAM: RAHEEM STERLING
The youngster is improving all the time after a turbulent summer and is in red-hot form, having scored a hat-trick in City's last Premier League game.
There were question marks over whether he'd be able to nail down a regular first-team spot at City, but the Englishman has quickly established himself.
Honourable mention must go to Ander Herrera, who is an underrated player. The Spaniard showed his worth against Everton last week and only narrowly misses out to Sterling in this XI.
ST: ANTHONY MARTIAL
With Aguero out for a month and Wayne Rooney in the worst form of his career, the striker spot can only go to one of Wilfried Bony or Martial.
Bony scored twice against Bournemouth last week, but with respect to Eddie Howe's men, the Ivorian will face higher standards of opposition this season.
Meanwhile, in the red half of Manchester, the 19-year-old Martial continues to impress. The Frenchman has made a sensational start to life at United, scoring five goals so far.
He was pushed out to the wing against Everton, but he's at his most dangerous when deployed up front.