Papiss Demba Cisse has been tearing defences apart since his move in the January transfer window, with a pair of stunning strikes in Wednesday's 2-0 win at Chelsea taking his tally to 13 goals from 12 games.
If City can keep Cisse quiet and follow up its crucial 1-0 victory over United on Monday with a win at St. James' Park on Sunday, Roberto Mancini's side will likely go on to claim a first title since 1968.
"Newcastle will be our hardest game — harder than United," Mancini said. "It is strange but it is like this.
"They have had a fantastic season and are playing to get into the Champions League."
With two matches remaining, City is ahead of United on goal difference, while Newcastle is level on points with fourth-place Tottenham having been tipped by many to struggle this season after selling many of its big-name players over the past 18 months.
Manager Alan Pardew's signings have been shrewd, however, none more so than Cisse, whose 10 million pound ($15.3 million) price tag looks to be a bargain based on his current form.
Many of his goals have been among the best in the Premier League this season, but his second against Chelsea — a swerving, 25-yard effort from an implausible angle — will probably stand out as the finest.
"I'm looking forward to seeing the highlights video of our season because there will be some great goals on there," Pardew said.
Newcastle has already beaten United at home, a 3-0 win in January, and has won eight of its last nine matches to leave the team challenging for a spot in Europe's premier competition after only two seasons back in England's top division.
Arsenal is one point clear in third, which could be the last Champions League spot available given that Chelsea could qualify by beating Bayern Munich in this year's final on May 19.
City, though, has rediscovered its form of the first half of the campaign and managed to handle the intense pressure during its must-win match against United.
"Beating United has given us the confidence we need for the last two games," City midfielder David Silva said. "It has been a very long and tough season. The Newcastle game is like a final for us now. We have to win it."
With City's final match coming at home to lowly Queens Park Rangers at home, United's hopes of defending the title could be virtually over this weekend.
The 20-time champions are at home to Swansea on Sunday — minutes after the final whistle of the City-Newcastle match — before a visit to Sunderland on the last day of the season.
"Monday night was a blow to us. We can only do what we can now and hopefully win our game on Sunday," United manager Alex Ferguson said.
"By the time we kick off we'll know what we'll need to do. The challenge for City is to win at Newcastle. Their form is good and it won't be an easy game for City. We'll be aware of the game going on before ours. You can't avoid it."
Arsenal hosts Norwich in the only league match on Saturday, which has been largely kept free for the FA Cup final between Chelsea and Liverpool at Wembley Stadium later in the day.
Tottenham travels on Sunday to Aston Villa, which has been dragged into a relegation scrap that has already done for Wolverhampton Wanderers.
Next-to-last Blackburn could be relegated if it loses on Monday to fifth-bottom Wigan, which is level on points with Villa. Bolton, the other team in the relegation zone, hosts West Bromwich Albion and is on the same points as QPR, which is at home to Stoke.
Also Sunday, Wolves host Everton and Sunderland visits Fulham.