Here's a look at three things to watch from the Niners' perspective:
1. A last chance for Kaepernick?
The possibility is very real that Sunday's game is quarterback Colin Kaepernick's last with the 49ers. Kaepernick can opt out of his contract after the season, and he's expected to. That doesn't mean Kaepernick won't return, but it wouldn't hurt his cause, both for a return and for a free-agent market to form, if he could put together a strong performance against the Seahawks.
Recent history shows that won't be easy. Kaepernick is just 1-5 in regular-season starts against Seattle, with two touchdowns and seven interceptions. He hasn't thrown a touchdown pass in his past three appearances against Seattle.
If ever there's going to be a time for Kaepernick to have a good game against the Seahawks, this might be it. Seattle has been without free safety Earl Thomas because of a leg injury, and hasn't come up with an interception in any of the three games he's missed the past few weeks. Likewise, Seattle is 1-3 this season without Thomas.
Going deeper, the Seahawks' pass defense is allowing 8 yards per attempt without Thomas, compared to 6.9 with him. In 11 games with Thomas in the lineup, the Seahawks allowed nine touchdowns and came up with 10 interceptions. In four without him, they've given up six touchdowns and have one interception.
The Niners have the least effective passing attack in the NFL and the Seahawks, even without Thomas, are stingy. But if San Francisco is to pull off an upset, they'll need a finishing flourish from Kaepernick & Co.
2. Pushing the pocket
The 49ers' pass rush has been inconsistent, though they're tied for 18th in the league in sacks. That pass rush has been a bit better recently, though, with 11 sacks in the past three weeks, tied for second-most in the NFL in that span.
That could be a good recipe for Sunday considering Seattle's struggles protecting quarterback Russell Wilson. According to ESPN Stats & Information, Wilson and Pittsburgh's Ben Roethlisberger are the only two quarterbacks in the past 25 years to be sacked at least 40 times in four consecutive seasons.
In Wilson's case, it's because of a shoddy offensive line that still hasn't been able to work out the kinks despite some recent investments via the draft. The Seahawks are on pace to finish last in ESPN's pass-protection metric for the third straight season. The offense has controlled the line of scrimmage on just 41 percent of pass plays this season, and that number has actually gotten worse lately, dipping to 38.8 percent.
Niners defensive end DeForest Buckner has been especially effective lately, and he has a chance to surpass his preseason goal of six sacks by bringing down Wilson behind the line just once. If the Niners can get after Wilson consistently, it would give them a chance to force him into mistakes, something Wilson has done much more on the road this season.
3. Who runs it?
The 49ers will be without running back Carlos Hyde, who suffered a sprained left MCL last week and was placed on injured reserve. That's a big blow for an offense that has rushed for the third-most yards (759) and averaged the second-most yards per carry (5.62) in the league since Week 12.
Without Hyde, the Niners will turn to backups Shaun Draughn, DuJuan Harris and, possibly, Mike Davis to fill the void. Draughn had some good moments this season as a receiver but has remained mostly ineffective on the ground, averaging just 2.92 yards on 53 carries.
As always, running against the Seahawks is not easy. They are eighth in the league in rushing yards allowed per game (95) and first in yards allowed per carry (3.48). Even without Thomas, Seattle remains committed to stopping the run first and has actually been even better than usual against the run, giving up just 3.08 yards per carry in the past three games without him.
It's reasonable to expect yards to be at a premium in general for the Niners in this one, but they have to be able to at least keep the Seahawks honest in order to check the first box on this list in their favor.