The 27-year-old had scans on Friday that revealed the left knee injury is serious enough that he is unlikely to be back in action until mid-December, although he does not require surgery.
However, the Belgium worldwide sustained an issue with his opposite knee during a coming together with Timothy Fosu-Mensah, and it has left the playmaker facing another spell on the sidelines.
De Bruyne only recently returned from another knee problem that forced him to miss two months this season, limiting the Belgium global to five appearances.
De Bruyne limped off in the closing minutes of City's 2-0 victory at the Etihad Stadium after falling awkwardly in a clash with Timothy Fosu-Mensah. "We want him", Guardiola told a news conference.
"He knows the desire we want for all young players".
As is the norm, De Bruyne is likely to head for Barcelona for rehabilitation.
He will miss Sunday's clash with Southampton, Wednesday's Champions League game with Shakhtar Donetsk and the derby with United, and is a doubt for the trip to Chelsea on December 8.
De Bruyne was making just his second start of the season, though City have moved top of the Premier League without him.
Belgium then have UEFA Nations League games against Iceland and Switzerland during the worldwide break. "The Kevin we know", he added of the midfielder who started last week's Champions League win over Shakhtar Donetsk and came on at Tottenham.
"And maybe that is going to help us in the last part of the season - he will be fresh and his body and help us reach our targets".