Sherman sustained the injury during the second quarter of Sunday's 38-27 loss to the Kansas City Chiefs. The 30-year-old needed assistance to help him to the locker room, did not return to the contest and was spotted with his left foot in a walking boot.
Prior to his departure, Sherman recorded two tackles and broke up a deep pass intended for Chiefs wide receiver Tyreek Hill.
Sherman was playing in his third game since tearing his right Achilles in November. He also had surgery to remove bone spurs from his left ankle in the offseason.
The 6-foot-3, 195-pound Sherman has collected seven tackles and a fumble recovery this season after signing a three-year, $39 million free-agent contract with the 49ers. That deal was signed two days after he was released by the Seattle Seahawks.
Sherman helped the Seahawks win a Super Bowl title following the 2013 season and led the club back to the championship game the following year.
Sherman was a fifth-round pick (No. 154 overall) out of Stanford in 2011. He has 32 interceptions and 101 passes defensed in his career.