The seven-year veteran was injured in the second half of the 49ers' 31-3 pummeling of the Cleveland Browns on Monday and had to be carted off the field.
Juszczyk will get a second opinion on the knee, as the team holds out hope that he could beat the four-to-six-week timetable, a source told NFL Network's Tom Pelissero.
The Harvard product has been a key piece of the 49ers' potent run game, a group that leads the NFL through five weeks with a whopping 200 yards on the ground per game. Juszczyk has been instrumental in leading three different San Francisco backs to 80-plus yard rushing games this season.
The Medina, Ohio, native is not known for carrying the ball - which he's done just once for 6 yards so far this season - but has been a Pro Bowl selection for the last three consecutive years because of his blocking prowess.
The 49ers will face a tough test when they head to Los Angeles to take on the defending NFC champion Rams in a Week 6 divisional tilt.