De Jong sustained a calf injury shortly after the Magpies' tour of New Zealand and was not involved in their final four pre-season matches.
It had been hoped he would be fit to take at least a place on the bench for Sunday's season-opener against City, but Alan Pardew has revealed the Dutch midfielder will not be involved at the weekend.
"Siem will not play against Manchester City, but should be back against Aston Villa," confirmed the Newcastle boss.
Cheik Tiote will also be absent on Sunday with a hamstring injury, with Davide Santon, Ryan Taylor and Papiss Cisse also unavailable.
"It's another week for Cheik, although it's nothing too serious," said Pardew. "Papiss is working with us again, although Santon is a little more long term.
"We're not that far away from a full-strength squad, and we'll cope without Tiote and de Jong because we've known for a few days they would not be playing.
"They'll be a miss but we'll be able to cope and it's nice to say that this season."
This is the second season in a row in which Newcastle face Manchester City in their opening game, but Pardew is confident his current squad is in a much better position than was the case 12 months ago.
Back then, Yohan Cabaye was effectively on strike as he attempted to force through a move to Arsenal, and Newcastle lost 4-0 in a game that saw Steven Taylor sent off.
"At the time, we were in dispute with our midfield player," said Pardew. "When we got off that bus, was he going to play or was he not going to play? The difference now is we're much more settled.
"The disruption of that unsettled us, and we lost a player (Taylor) in the first half, which is maybe a consequence of the frustration we were all sharing.
"We have a new-found sense of belief now and players grow when they see new signings. If you see more quality around, you feel more confident."