The Hawks revealed on Thursday that Lewis suffered the setback at training and is tipped to miss his side's Round 1 bout with Essendon on March 19.
The club is set to continue to monitor the knee strain, with Lewis unlikely to require surgery.
The injury is not related to the knee problems that limited Lewis' 2022 campaign to 15 games, however the ACL strain is located on the same knee.
"We will monitor Mitch's progress closely over the coming weeks," head doctor Liam West informed the club.
"He will certainly spend some time on the sidelines though and, at this stage, we expect him to miss Round 1.
"Whilst this is the same knee he injured last season, it is an unrelated injury."
The setback is an early blow to Sam Mitchell's planning for the 2023 season, with Lewis the Hawks' focal point in attack.
Lewis booted 37 goals last year in what was a breakout season for the tall forward, with the Wallan product expected to reach new heights this year as a leader among Hawthorn's attack.
The 24-year-old re-signed with the Hawks in June last year, recommitting to the club until the end of 2026.
Hawthorn's Round 1 encounter with the Bombers is scheduled for Sunday, March 19 at the MCG.