The Magpies, of course, won the competition last year, beating Arsenal in the semi-finals before seeing off Liverpool in the final at Wembley.
But in Man City, United face a side that Eddie Howe has called the “hardest team to play over two legs in the country”.
“I think the natural preference is for the home game to be the second leg, just because you have a clear understanding of what you need to do and you have the home crowd with you,” Howe said. “It's not like that for us this time.
“We need to use the home crowd for our advantage in the first game and try and give everything to impose ourselves on them in this home tie. It's going to be an important game for us.
“We really enjoyed the two-legged format last year. Even the gap between games was quite good because you could detach yourself from the result and your focus goes away and then it comes back when it comes round. It's very similar again this year, so we enjoyed that challenge.
“This is going to be a totally different one. I think Manchester City are the hardest team to play over two legs in the country. Pep, I'm sure, will tactically have something ready for us and we'll have to be at our very best to try and get through.”
And Newcastle’s task has made harder by the number of defensive injuries and the lack of recovery time, having 72 hours ago played 120 minutes and penalties to get past AFC Bournemouth in the FA Cup third round.
Howe added: “I'll have discussions with the medical team, performance team, the players themselves, because physical wellbeing and the energy levels, I think, are of the utmost importance in this game.
“It wasn't ideal, the 120 minutes, certainly from our perspective. We knew this game was here, but we wanted to get through. I think that was the priority and whatever it took, we had to do.
“And then we had to, the last couple of days, to look back and reflect and to then plan this game with hopefully a fresh team and one that can play how we want to play.”
Here’s how Newcastle United are predicted to line-up against Man City:
Aaron Ramsdale was the hero against Bournemouth and has played every Carabao Cup game so far, but given the magnitude of the game, Howe will want his No.1 in goal.
1. GK: Nick Pope
Aaron Ramsdale was the hero against Bournemouth and has played every Carabao Cup game so far, but given the magnitude of the game, Howe will want his No.1 in goal. | Getty Images
A central midfielder by trade but the 19-year-old has been a revelation at right-back amid the injury crisis.
2. RB: Lewis Miley (in for Kieran Trippier)
A central midfielder by trade but the 19-year-old has been a revelation at right-back amid the injury crisis. | Getty Images
Having started the last 26 games, Thiaw could probably do with a rest but the lack of defenders won’t allow it.
3. CB: Malick Thiaw
Having started the last 26 games, Thiaw could probably do with a rest but the lack of defenders won’t allow it. | Getty Images
Played 120 minutes at the weekend on his first start in two months. Not ideal, and even less ideal that he’ll have to go again less than 72 hours on.
4. CB: Sven Botman
Played 120 minutes at the weekend on his first start in two months. Not ideal, and even less ideal that he’ll have to go again less than 72 hours on. | Getty Images