Samuel's leg bent awkwardly underneath him when he was tackled on a running play. The 49ers' medical staff had to call out a cart to bring Smuel back to the locker room.
Deebo was visually extremely emotional after the event.
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Samuel's injury comes a week after quarterback Jimmy Garoppolo suffered a broken left foot that is expected to keep him out for the rest of the season.
Samuel had four catches for 43 yards and four carries for 21 yards and a touchdown at the time of his injury.
San Francisco led 28-0 at the half.