Mourinho is reeling from United's 4-0 humiliation by his former club Chelsea, while City manager Guardiola has gone five games without victory for only the second time in his stellar coaching career.
Both managers are expected to rotate their squads for the fourth-round meeting beneath the Old Trafford floodlights, but Guardiola says neither side can afford to take the game lightly.
"I think everyone can believe this competition is not the big one, but I am going to prepare to win the game," he said.
"For the players who play, we'll be depending on them to make the best performance possible. It is a final.
"I don't understand my job if I play a game thinking another game is more important. This is the most important.
"But at the same time, I have to consider how the condition of the players is. Three days after it is West Brom, then Barcelona, and they are so important as well."
The context was quite different when Guardiola and Mourinho renewed their sulphurous rivalry at Old Trafford on September 10.
Guardiola had won his first five games at the City helm since arriving from Bayern Munich and Mourinho also boasted a 100 percent record after four matches of his United tenure.
City prevailed 2-1, a victory founded upon a dominant first-half display, to confirm their status as early title favourites.
But they have gone off the boil since late September, losses to Tottenham Hotspur and Barcelona and draws with Celtic, Everton and Southampton leaving Guardiola scratching his head.
They remain top of the league, but on goal difference alone.
United's defeat by City plunged them into a negative spiral, the derby reverse followed by successive losses away to Feyenoord and Watford.
A six-game unbeaten run appeared to represent a turnaround, but at Chelsea on Sunday Mourinho was dealt his heaviest defeat since a 5-0 loss to Barcelona's Guardiola with Real Madrid in November 2010.
While Guardiola has long taken up residence with his family in a city-centre flat, Mourinho is still staying at Manchester's Lowry Hotel.
His family remain in London and he admitted on the eve of Wednesday's game that the situation is far from ideal.
"You know the history of the paparazzi," he said in a Sky Sports interview.
"For the hotel and the brand that sponsors me, the clothes brand, it's amazing because they are there every day.
"Everybody knows the name of the hotel. Everybody knows the last arrivals of that brand. So, for them, it is amazing.
"For me, it's a bit of a disaster because I want sometimes to walk a little bit and I can't. I just want to cross the bridge and go to a restaurant. I can't, so it is really bad."
Mourinho is certain to be without Ivorian centre-back Eric Bailly, who will be sidelined for around two months after damaging knee ligaments at Chelsea.
Captain Wayne Rooney is a doubt after missing the trip to Stamford Bridge with a muscle injury, but close-season signing Henrikh Mkhitaryan could make his first appearance since September's derby.
Playmaker Kevin De Bruyne is out for City due to a calf injury and Willy Caballero is expected to replace Claudio Bravo in goal.
Injuries to Bacary Sagna and Pablo Zabaleta may leave Guardiola with a problem at right-back, although he could persevere with the three-man defence he used in Sunday's 1-1 draw with Southampton.
Youngsters Tosin Adarabioyo, Angelino, Pablo Maffeo and Aleix Garcia are in contention to play, but Guardiola said he would not field too many untested players.
He said: "To put three, four or five young players in at the same time is not good in that moment (when the team are under-performing) because you have to protect them."