Niners GM John Lynch told KNBR-AM radio on Friday morning that McKinnon would be out of action until Week 1.
McKinnon suffered a leg injury during Sunday's practice and underwent an MRI exam. Coach Kyle Shanahan said Monday that the running back strained his calf.
"The good news is it's not going to be long-term, the bad news is it's going to take him up to Week 1, our opener, so his opportunity to get more in rhythm in our system, that kind of goes out the door," Lynch said. "But he's played a lot of football, and we play a lot of football in the offseason, OTAs and all that, so we're going to have to trust that he's going to be ready."
Holding out McKinnon until the start of the season was the expected move for the 49ers. San Francisco gave McKinnon a four-year $30 million contract to be a dual-threat back in Shanahan's RB-friendly system. Even if it hurts his early-season production to miss reps in a new offensive system, the 49ers won't risk re-injury during the preseason.