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De Bruyne limped off in the second half of Saturday's 1-0 FA Cup semi-final defeat by Chelsea, which ended City's hopes of a historic quadruple.
The 29-year-old's injury is badly timed for City as they try to retain an eight-point lead over second-placed Manchester United, while looking to win the Champions League and League Cup.
City travel to Villa, then play Tottenham in the League Cup final on Sunday before the first leg of their Champions League semi-final against Paris Saint Germain on April 28.
"Manchester City can confirm that Kevin de Bruyne suffered injury to his right foot and ankle in Saturday's FA Cup semi-final against Chelsea," a City statement said on Monday.
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"The extent of the problem is not yet known.
"Kevin will continue to be reviewed but will miss Wednesday's Premier League trip to Aston Villa.
"We will bring you further updates on his condition in due course."
De Bruyne, who has scored eight times in 32 appearances this season, has been a pivotal player since he joined from Wolfsburg in 2015, winning seven major trophies with City.
He signed a two-year contract extension earlier this month that ties him to the club till 2025.
Belgium coach Roberto Martinez will be watching nervously too as his country are among the favourites to win the delayed Euro 2020 later this year.
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