Lupoi's departure adds another hole for Alabama head coach Nick Saban to fill on his coaching staff.
Since the Crimson Tide lost in the College Football Playoff National Championship to Clemson on Jan. 7, offensive coordinator Mike Locksley (Maryland), co-offensive coordinator Josh Gattis (Michigan), quarterbacks coach Dan Enos (Miami) and offensive line coach Brent Key (Georgia Tech) have all left.
The Browns hired Freddie Kitchens, a former Alabama quarterback, as their head coach this week.
Fox Sports was first to report Lupoi's departure.
Pete Golding, Alabama's co-defensive coordinator, is likely to be elevated to the primary coordinator and playcalling role, according to sources. Golding was involved in playcalling in 2018, his first season the staff.
Another coach who will be remaining with Alabama is Butch Jones, sources told ESPN.
Jones, who spent last fall as an offensive analyst for Saban, will stay in a role still to be determined. The former head coach at Tennessee, Cincinnati and Central Michigan could fill one of Alabama's offensive position coach vacancies or be in a senior analyst or advisory position.
Jones had been mentioned as a candidate to join Maryland's coaching staff under Locksley. But Maryland on Wednesday announced three offensive staff hires, including coordinator Scottie Montgomery, most recently the head coach at East Carolina.
ESPN's Chris Low and Adam Rittenberg contributed to this report.