Grandal, who was thrown out by Myles Straw, was unable to put any weight on his leg as he was helped off the field.
Grandal was on crutches in the clubhouse and said he wouldn't know the specifics of his injury until undergoing tests. Manager Tony La Russa said he will be placed on the injured list Sunday.
Meanwhile, outfielder Eloy Jimenez (right knee hyperextension) batted third and served as the designated hitter, one night after exiting in the middle of an at-bat in the eighth inning. Jimenez said he responded well to treatment after being injured on a hard swing.
Grandal, 33, is batting .203 with three home runs and 21 RBIs this season.
Chicago, which had lost three in a row, moved within 2½ games of the Guardians, who lead the American League Central by one game over the Minnesota Twins.
The Associated Press contributed to this report.