The Seahawks, already double-digit underdogs, will try to snap a three-game losing streak and avoid falling any further out of the NFC playoff picture with their backup quarterback.
The Seahawks have running backs Ken Walker III (oblique) and Zach Charbonnet (knee bruise) available after both were listed as questionable. Walker has missed most of the past three games. Linebacker Jordyn Brooks (ankle sprain) is also active after being listed as questionable.
Tre Brown, the Seahawks' third cornerback, is among their inactives with a heel injury.
Smith was listed as questionable after hurting his groin in practice Thursday. He suffered what is roughly considered a two-week injury, a source told ESPN's Adam Schefter, but wanted to try to play through it against San Francisco. A source told ESPN on Saturday that Smith would work out Sunday morning but that his chances of being able to play weren't looking good.
Smith has also been dealing with a triceps contusion on his throwing arm from the Seahawks' Nov. 19 loss to the Rams and said before practice Thursday that he was still "not close" to 100 percent, but his questionable designation was tied only to his groin injury.
Seahawks general manager John Schneider said Smith is "doing good" but the team decided they didn't want to make the injury worse.
"He tried going and he was out here early this morning working out," Schneider told Seattle Sports 710-AM. "He had an unfortunate situation in practice where he kind of over-extended and got tripped up a little bit. He tried going and we don't want to make it worse, so he's not going to go today. We were able to get [quarterback] Sean Mannion back on our practice squad and elevate him yesterday. I think people are excited to see Drew. Drew's getting his opportunity and has the keys in his hand for a couple days now, so here he goes."
Lock, 27, will make his first start as a Seahawk. Acquired from the Denver Broncos in the Russell Wilson trade in March 2022, Lock didn't play a regular-season snap last season after Smith beat him out for the starting job. Lock has completed 4 of 12 attempts for 66 yards and an interception over two brief appearances this season, both in relief of an injured Smith.
A second-round draft pick by Denver in 2019, Lock was 8-13 as a starter over his three seasons with the Broncos, throwing 25 touchdown passes and 20 interceptions.
"He's been waiting for this opportunity and looking forward to it and preparing for it," coach Pete Carroll said Friday. "If this comes to pass, then he is as ready as he can get. I'm excited about him getting a chance to play. I know for him, he's been really disciplined about the way he focuses every week to make himself know and believe that he's going to be playing."
In light of Smith's groin injury, the Seahawks re-signed Sean Mannion to their practice squad Friday and elevated him for Sunday's game.
Seattle's other inactives: outside linebacker Frank Clark Sr., wide receiver Dee Eskridge (ribs), offensive tackles McClendon Curtis and Raiqwon O'Neal, and linebacker Patrick O'Connell. The Seahawks announced Saturday that Clark wasn't making the trip to the Bay Area and that he would be inactive for noninjury reasons.
The Seahawks (6-6) were 14.5-point underdogs to the 49ers (9-3) as of Sunday afternoon, according to ESPN BET. San Francisco beat Seattle 31-13 at Lumen Field on Thanksgiving night and has won four straight games over the Seahawks by a combined score of 120-56. The Seahawks have not lost four straight games since Carroll became their head coach in 2010.