Smith suffered the injury about midway through Saturday's practice as he chased down running back Matt Breida near the sidelines.
The Smith injury could now open the door for rookie linebacker Reuben Foster, who was selected by San Francisco with the 31st overall pick in the 2017 National Football League draft.
While 49ers coach Kyle Shanahan inititlly suggested Smith would miss an extended period, an MRI later revealed the severity of the injury and confirmed the blow to the team's defense after signing the veteran to a five-year contract worth $26.5 million in March.
"Neither one of them are good news", Shanahan said.
He appeared in 15 games for San Francisco last season as a rookie, starting 11 of them at right guard.
Foster was projected to be a top-15 pick in the 2017 NFL Draft, but questions regarding a shoulder injury led to him falling to the bottom of the first-round. "I think at linebacker you have to smart, patient, know when you can shoot your gun and go make those plays".
Malcolm Smith's season is over before it even started.
Garnett, who has been working with the first-team offense at left guard, is dealing with a left knee that could require a "clean-up" type of surgery. The Niners have no shortage of bodies along the offensive line, but many are journeymen who have been mediocre or worse for a long time. Zane Beadles filled in for him with the first-string defense Saturday. But if Smith's injury is serious, the team isn't really left with any other choice.