Safety Lamarcus Joyner also will be sidelined as he recovers from an ankle injury suffered in Week 16.
"Those guys are making progress, but we don't feel like it's going to be at the point where they're ready to go," McVay said. "So we want to continue to be smart with that."
The Rams (12-3) have clinched their division but need a victory over the 49ers (4-11) to secure the No. 2 seed in the NFC and a first-round bye in the playoffs. If the Rams lose Sunday, they'd still secure the No. 2 seed if the Chicago Bears lose to the Minnesota Vikings.
Veteran running back C.J. Anderson, whom the Rams signed on Dec. 18, will make his second start. On Sunday, Anderson rushed for 167 yards -- 1 yard shy of tying his career best -- and a touchdown in a victory over the Cardinals.
With the playoffs looming, McVay downplayed any concern about Gurley's knee, which also flared up after a Week 1 victory over the Oakland Raiders.
"I would think so," McVay said, when asked if Gurley would be available for the playoffs. "But if you said a couple weeks ago that we would have to hold him out for the last two weeks, I probably would've been surprised about that. But based on the information that we're getting, there isn't any reason for us to press the panic button or think that he won't be available."
Gurley has scored a league-best 21 touchdowns this season and ranks second in rushing yards with 1,251 despite not playing in Week 16.