The playmaker is due to undergo surgery and is facing a significant spell on the sidelines after injuring his anterior cruciate ligament in training on Wednesday.
Buendia was entering his third season at Villa Park and was a key part of Unai Emery’s plans.
Those will now be forced to change, with Villa expected to enter the transfer market to source a replacement for the Argentina international.
Buendia became Villa’s then club record signing when he joined from Norwich for £33million in the summer of 2021 and made 73 Premier League appearances in his first two seasons at the club.
Midfielder Aaron Ramsey is, meanwhile, on course to complete a £14m move to Burnley in a deal which will also include a buy-back clause.
Villa start their Premier League campaign at Newcastle on Saturday.