Ederson was forced to come off during their 1-1 Premier League draw with Liverpool following a challenge on Darwin Nunez, conceding a penalty.
Meanwhile, De Bruyne has a groin strain which resulted in him being left out of Belgium's squad for friendlies with Ireland and England this month.
"Kevin's not ready. He already played in Anfield with some problems. But he's getting better. He's not ready for tomorrow. We spoke with Belgium manager Domenico Tedesco and he decided," Guardiola told reporters ahead of Saturday's game.
"I'm grateful because he didn't feel good and he could recover for the rest of the season. He played well (against Liverpool). All the players have problems, but the day after he didn't feel good, it's better to take care.
"Eddie (Ederson) is getting better, hopefully he'll be ready after the international break. Tomorrow, for sure (he will not play). He'll have two weeks off then, he'll recover, we'll see how he feels."
Guardiola also confirmed Jack Grealish has returned from a groin injury and will be a part of the squad. Grealish has not played since their 6-2 win over Luton Town in the FA Cup fifth round.
City are facing Newcastle for the fourth time this season, having beaten them twice in the league, but Eddie Howe's side knocked them out of the League Cup in September.
"This season and previous ones, since Eddie Howe was there and the people from Saudi Arabia took over (the club), it's always been tight games. We don't expect anything different," Guardiola said.
"We have an incredible chance at home with our people. We need the support of our fans in home games like we had against Manchester United (in a 3-1 comeback win), I don't remember that environment for a long time.
"Tomorrow isn't an exception. We need it to reach the semi-final at Wembley again."
Gordon injury not serious
Newcastle United winger Anthony Gordon's knee injury is not serious and he could play against Manchester City, manager Eddie Howe said on Friday.
Gordon earned his first England senior call-up on Thursday for the forthcoming internationals against Brazil and Belgium, although there were doubts over his fitness.
The 23-year-old was forced off in the 3-2 Premier League defeat by Chelsea on Monday and there were fears that he could have suffered a serious injury.
But Howe was upbeat ahead of the clash at City.
"It was a strange one because initially when you see a player come off like that you do fear that there is a serious injury," Howe told reporters. "But he partly trained yesterday, he joined in and did okay so I don't think he did anything serious which is great news for us.
"We train again today, we will make a judgement after that."
Gordon has impressed this season and England manager Gareth Southgate has rewarded him with a chance to stake a claim for inclusion in his squad for the European Championship.
"Delighted for him as I know it's been a big ambition of his," Howe said. "He deserves it, he's been outstanding this season and grown week on week, I'm delighted that's been recognised. He has worked so hard . He scored goals, creates goals and has done brilliantly for the team."
Of more concern for Howe is Newcastle's defensive problems as they try to keep their season alive by pulling off a shock win at The Etihad Stadium.
"We've analysed (Monday's defeat) and gone through it and reflected on it, now we are going to the best team in the country in my opinion and we will need a big improvement in our defensive resilience."