Ledezma, 20, picked up the knee injury playing for PSV Eindhoven in their Europa League match at Omonia Nicosia on Thursday.
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PSV say the injury will require "months of rehabilitation" and have ruled him out for the rest of their campaign.
The news comes as a blow both for Ledezma, PSV and the USMNT. He broke into PSV's first team this season, making six appearances. He also made his senior USMNT debut in their friendly against Panama in November, where he contributed two assists from the bench.
The timetable for recovery means he will likely miss the USMNT's Olympic qualifying matches and is a doubt for the tournament itself if Gregg Berhalter's side make it to Tokyo.
Ledezma could also be out for the Nations League finals next June, the Gold Cup in July and August as well as the start of World Cup qualifying in September.
Ledezma was forced off after 17 minutes against Omonia Nicosia after a tussle for the ball near the touchline. PSV manager Roger Schmidt said after the match, prior to the scan on Friday: "We have to think that this is a big injury, it's not a small one. He [Ledezma] had a lot of pain in that moment, and after the match still a lot of pain.
"The win tonight was for Richy, because he's a really good person, really good player, and we all will help him to come back very soon."