Three weeks ago, United already had one hand on a record 20th title after City's defeat at Arsenal left Sir Alex Ferguson's team a hefty eight points clear with only six games remaining.
But a poor run of results from United, which has seen them take only four points from a possible nine, has suddenly given City the chance to put themselves back on pole position as the finish line looms into view.
An estimated worldwide television audience of more than 650 million is expected to tune in for a match that is being hyped as the biggest in Premier League history.
"This is the derby game of all derby games," Ferguson said. "It's in the blood of the supporters and I know lots of fans who would give everything to win this game," the United manager added.
City midfielder Gareth Barry also emphasised the unique nature of the top-of-the-table duel.
"People are speaking of this as being the biggest game in Premier League history and it's a massive game to play in," Barry said.
"I don't think you can get away from the size of the game against United and the pressure."
The equation for City is simple: a victory on Monday would see them return to the top of the table.
Wins at Newcastle and at home to Queens Park Rangers would then guarantee City the title, provided United are unable to make up their rivals' significant advantage in goal difference, which currently stands at plus six.
City manager Roberto Mancini has attempted to douse the expectation level by stating that United will remain favourites for the title even if they lose, citing the champions' final two matches against Swansea and Sunderland.
"I think they have more chance than us because we play the derby on Monday, after we play against Newcastle, that will be a very tough game," Mancini said.
"Instead United play Swansea and Sunderland. For them, they will be two easy games."
Ferguson meanwhile is relishing the challenge from opponents he views as the biggest threat to United's position at the summit of the English game owing to the club's seemingly limitless wealth.
United have already demonstrated that they have the know-how to get a result at a ground where City have dropped just two points all season, winning January's FA Cup third round tie 3-2.
Yet Ferguson must be concerned by the sudden frailty of a United defence that was punctured repeatedly by Everton last weekend in a 4-4 draw.
City, who humiliated United 6-1 at Old Trafford in October, have rattled in 12 goals in their past three games, and their nimble strikeforce of Sergio Aguero and Carlos Tevez will fancy their chances of adding to that haul if Rio Ferdinand and Jonny Evans have another off-day.
Of all the storylines to emerge from this year's Premier League page-turner, it is the re-emergence of Tevez that is potentially the most compelling.
Ostracised by Mancini after his infamous refusal to warm-up during the Champions League defeat at Bayern Munich in September, the former United striker then disappeared to Argentina for three months of unauthorised leave.
Mancini, who had previously said Tevez would never play for the club again, has been forced to reverse his stance during the run-in, particularly after ill-discipline saw Mario Balotelli sidelined for three games.
Tevez has responded to his recall by delivering goals, adding an injection of verve to a City forward line that had been struggling to reproduce their scintillating early season form.
Tevez, who is expected to seek a move this summer, will be putting his talents on show to a mammoth worldwide audience on Monday, with a record 16 broadcasters airing the match live.
"The interest in this game from around the world is unprecedented," a City spokesman said.