McCaffrey was listed as questionable for Monday’s game after being limited throughout the week in practice, but he will now miss his first game due to injury since joining the 49ers in Week 7 of the 2022 season.

On Aug. 6, head coach Kyle Shanahan announced McCaffrey was dealing with a calf injury and that the team would be cautious with his health, leading to CMC being held out of each preseason game and most of the 49ers’ training camp practices.

However, McCaffrey spoke to the media on Friday, which is often a positive foreshadowing.

Jordan Mason and rookie Isaac Guerendo will now be looked on to shoulder the load at running back with veteran Elijah Mitchell out for the season and CMC sidelined Monday night.

McCaffrey won the NFL rushing title last with 1,459 yards and tallied league highs of 2,023 scrimmage yards and 21 scrimmage TDs en route to being voted AP NFL Offensive Player of the Year.

Just how long one of the league’s finest talents is out remains to be seen.

For now, he’ll be looking on in street clothes as the 49ers aim to get off to a winning start tonight when San Francisco kicks off against New York at 8:15 p.m. ET.