Grealish has not featured in City's last three league games after suffering a groin injury in the Champions League win at FC Copenhagen, and the midfielder went off injured in the first half after starting Tuesday's FA Cup win over Luton Town.
"No, he will not be fit for the weekend. When he comes back I don't know," Guardiola told a press conference.
"Setbacks are always there in life, he will overcome it."
Guardiola doesn't expect Grealish to return before the international break later this month when England play two friendly games with Brazil and Belgium.
"No, I don't think so. He has to recover well to use him as much as possible," he said.
"I didn't speak to Gareth Southgate."
City now face a tough run of games in the coming weeks, after United on Sunday they will face their title rivals Liverpool and Arsenal in the league, along with their Champions League last 16-second leg with Copenhagen on Wednesday.
"And Aston Villa, how nice. I prefer that than the opposite. Key players, we have 20 key players. I know what you're talking about but we have had key players out injured and still done well," Guardiola said.
"So nice to do the fixtures, a chance to get to the quarter-finals of the Champions League, then Anfield, a chance against Newcastle United (FA Cup), we work to arrive here to live these moments."
City are second in the standings, one point behind Liverpool and one point ahead of Arsenal, while United are in sixth place, 15 points off City, and Guardiola was asked when their Manchester rivals can expect to challenge for the title.
"(Co-owner) Sir Jim Ratcliffe and others know the diagnosis of the club. If Sir Jim said they need two or three years to be there, who am I to say the opposite?" the manager said.
"I'm sure they will work to close the gap."
Last season's treble-winners City are the dominant force in English football, something which Guardiola hopes to continue.
"In the Eighties it was Liverpool, the Nineties it was United, now we are this many years, winning seven Premier League titles in the last 11, 12 years," he said.
"It has happened, but in 50 or 60 years there has never in one country been a club that dominates and controls everything, so we can try to extend for as many years as possible what we are trying to do."
