He sustained the knee injury while making a cut at 49ers practice Saturday, per Nick Wagoner of ESPN.
"Something with a knee, we'll find out later," 49ers head coach Kyle Shanahan said before the diagnosis, per Wagoner. "We're nervous about it, that's for sure."
The 26-year-old previously gave the 49ers a scare when he suffered a knee injury late in training camp that required an MRI. Ultimately, the scans revealed a muscle strain, and he was given the all-clear to return to the field following some cautious maintenance work by the coaching and medical staffs.
Since then, San Francisco's $30 million man has been trying to work his way back to full strength in hopes of getting ready for a Week 1 tilt against the Minnesota Vikings.
The 49ers don't have another bona fide three-down back, so it will likely be up to Matt Breida and free-agent signee Alfred Morris to split the workload with McKinnon out.