An MRI on Saturday revealed the severity of the injury, and McKinnon will undergo surgery on his right knee. This season's workload will likely fall on backup running backs Matt Breida and Alfred Morris.
The 49ers signed McKinnon in March to a four-year deal worth up to $30 million. The versatile running back was to serve as the featured back within head coach Kyle Shanahan's offense.
The 49ers kick off the regular season on the road when they face the Minnesota Vikings at U.S. Bank Stadium on September 9.