The injury occurred during team drills. According to NBC Sports Bay Area, McKinnon was seen grabbing the back of his right knee.
San Francisco said McKinnon will need an MRI.
McKinnon is expected to shoulder the ground game after signing a four-year, $30-million contract in March. With Minnesota last season, McKinnon rushed for 530 yards and three touchdowns.
The top backup running back, Matt Breida suffered a shoulder injury in San Francisco’s preseason opener against the Cowboys.