Kolb was hurt when he faded to pass on third down and was hit by Justin Smith as he threw. He fumbled, but the Cardinals recovered. He was replaced by John Skelton, who threw for 282 yards and three touchdowns, and Arizona rallied to hand the 49ers their third loss of the season, 21-19 on Sunday.
Kolb was making his second start after missing four games with a right turf toe and bruise to the side of the same foot. The team announced early in the third quarter that Kolb would not return.
In Skelton's previous appearance against the 49ers he threw three interceptions and was benched after three quarters in a 23-7 loss on Nov. 20.
Information from The Associated Press was used in this report.