Linebacker Malcolm Smith returned to the sideline with an injured hamstring, while defensive end Solomon Thomas (head) and tight end George Kittle (shoulder) went back to the locker room in the first quarter for observation.
Backup running back Matt Breida also suffered a first-quarter shoulder injury.
The shoulder injuries have head coach Kyle Shanahan concerned, according to ESPN's Adam Schefter.
"I know it's going to be some time," Shanahan said of Breida and Kittle. "So, I don't know how long, but I have a feeling it's going to be some time."
Thomas was reportedly inadvertently kicked in the face with a cleat and ruled out of returning to the game.
--Field Level Media