The Citizens are in action before their title rivals, who host Leicester City 24 hours later, and can up the pressure on the Reds with a fifth top-flight win in a row.
"Disappointment" is the word Rafael Benitez used on the back of his side's latest FA Cup failure, as the Magpies once again missed out on the chance to give supporters reason to dream that a rare cup run could be on the cards.
Benitez made seven changes for the fourth-round tie against Watford - four fewer than the visitors to St James' Park - and saw his side fall to a 2-0 defeat to leave them battling on just one front in the final four months of another underwhelming season.
It was telling that owner Mike Ashley stayed away at the weekend, perhaps knowing what was to come. Still, Ashley's absence did not stop supporters venting their fury towards him, wherever he was in the world.
The defeat to Watford came a week on from Newcastle's impressive 3-0 victory over Cardiff City - a result that appeared to rejuvenate the club as they climbed out of the relegation zone at the expense of their opponents.
That is the first time United have netted three goals in a league game this term and it is also more goals than they had managed in their previous five matches in the competition, scoring just twice in that run.
Benitez will point out that his side faced - and lost to - Manchester United, Liverpool and Chelsea in that run, but there were was also a goalless home draw against fellow strugglers Fulham and a 1-1 draw at FA Cup conquerors Watford.
The win against Cardiff came at just the right time, then, leaving Newcastle two points above the dropzone ahead of this daunting visit of the champions.
Not since November have they managed back-to-back league wins, doing so with victories over Watford, Bournemouth and Burnley. Since then, Benitez's men have collected nine points from a possible 30.
A better omen for the Magpies is that they have won four of their last six home Premier League games against sides starting the day in the top two, however, losing only to Arsenal in December 2013 and Man City in December 2017.
Recent form in Premier League: DLDLLW
Recent form (all competitions): LDLWWL
In contrast to Newcastle's stuttering run of form, Man City have clicked into gear over the past month and are still on course for an unprecedented quadruple.
Since losing against Crystal Palace and Leicester City either side of Christmas, the Champions have won eight matches in a row, scoring 33 goals and conceding just twice since then.
In fact, City have scored 29 goals in all competitions since last conceding. That run spans back to the win over Liverpool on January 3, when Leroy Sane struck to cancel out Roberto Firmino's equaliser.
The Citizens are still playing catch up on Liverpool, who are themselves enjoying a good run of form, but they can close the gap to within a point if they come out on top at St James' Park on Tuesday evening - a huge psychological boost ahead of the Reds' home meeting with Leicester.
In the top flight, it is four wins in a row for Pep Guardiola's men, the last two of those by a 3-0 scoreline against Wolverhampton Wanderers and Huddersfield Town.
City have also brushed aside Burnley in the fourth round of the FA Cup and completed a 10-goal rout of Burton Albion in the EFL Cup, meaning that four trophies - despite Guardiola's best attempts to play it down - could still be heading to the Etihad Stadium before the season is out.
This midweek trip to the North-East will be Guardiola's 100th Premier League game in charge of City. The Catalan coach, widely considered to be the best in the world, has won 73 of those previous 99 matches - level with the record for most wins by a manager in their opening 100 matches in the competition, jointly held by Jose Mourinho.
Guardiola can move out in front in that regard with another victory this week and, more importantly, it will leave City in a very strong position as the final straight draws into sight. Any sort of slip-up, though, and it really will be Liverpool's title to lose.
Recent form in Premier League: LLWWWW
Recent form (all competitions): WWWWWW
De Bruyne could well retain his place in the side having now returned to full fitness, but Kyle Walker is in contention to return at right-back and Guardiola can also choose between Raheem Sterling, Sane and Mahrez out wide.
Another player in contention to return to the starting lineup is Benjamin Mendy, though the Frenchman is still struggling with a knee problem and his fitness needs to be monitored.
Up top, Sergio Aguero has scored 14 goals in his 12 Premier League appearances against Newcastle - more than any player has scored against an opponent for a single club in the competition's history.
Newcastle have a number of injuries to contend with, meanwhile, as Karl Darlow, Paul Dummett, Mohamed Diame, Jonjo Shelvey and Ki Sung-yeung are all on the sidelines, while Yoshinori Muto has been away on international duty.
With a number of midfield men unavailable, Isaac Hayden - desperate for a move away from St James' Park last summer - may start for a third match running.
Newcastle United possible starting lineup:
Dubravka; Yedlin, Lejeune, Schar, Lascelles, Ritchie; Perez, Longstaff, Hayden, Atsu; Rondon
Manchester City possible starting lineup:
Ederson; Walker, Stones, Laporte, Delph; De Bruyne, Fernandinho, David Silva; Sterling, Aguero, Sane
Head To Head
Newcastle are winless in their last 22 Premier League games against Man City, losing 19 of those - the Magpies' longest winless run and the Citizens' longest unbeaten run against any top-flight opponent.
City have taken 46 points from the last 48 on offer against United, scoring 45 goals and conceding nine.
We say: Newcastle United 0-2 Manchester City
Man City welcome Arsenal and Chelsea to the Etihad Stadium in their next two league matches, making three points in midweek all the more important. Newcastle tend to keep things tight against the division's top sides, including in the reverse meeting between the sides, but the champions should have enough in the tank to get the job done.