McCaffrey will be sidelined for at least six weeks with a PCL injury after coming out of the game during the second quarter in the Niners' 35-10 loss to the Buffalo Bills.
"It was frustrating," Shanahan said after the game. "He had a great week of practice and I could feel his urgency and stuff and thought he came out great, looking really good, and it looked like he just got his shoestring there. ... I hurt for him, and tough for our team not having him."
Backup running back, Mason, who was the starter for the Niners while McCaffrey was out, will be joining him on the IR with a high ankle sprain. Mason will miss four to six weeks, according to head coach Kyle Shanahan, leaving him out, at the very least, until the season finale against the Arizona Cardinals.
Third-string running back Isaac Guerendo will be tapped as the team's number-one back come Sunday against the Chicago Bears.
Guerendo scored the lone touchdown for San Fran on Sunday night against the Bills. Now, the rookie fourth-round pick out of the University of Louisville will be receiving the first start of his career.
Guerendo has 246 rushing yards and two touchdowns on 42 rushes this year, averaging almost six yards per attempt.
Mason led the Niners running back group with 789 yards this year with three touchdowns. Meanwhile, McCaffrey's list of career injuries continues to pile up as the star back could miss the remainder of the season.