In the eight games that have followed, the Seahawks have statistically been among the worst.
"The run game has been solid except for some big plays we've given up to really good players," Seattle coach Pete Carroll said. "We're hoping to play a lot cleaner, a lot sharper."
Over the first six games, the Seahawks were No. 2 in the NFL in yards rushing allowed per carry at 3.3 yards. That ability to stop the run put more pressure on the opponents passing game to find openings against Seattle's secondary.
But during the past eight games, the Seahawks have struggled. They're giving up 5.3 yards per carry, which ranks last in the NFL.
Part of the problem is the big runs Seattle's defense has allowed to running backs such as Adrian Peterson, Frank Gore and Reggie Bush.
In five of the past eight games, the Seahawks have allowed their opponent at least 100 yards rushing as a team, after not letting any of their first six opponents reach that mark.
Still, there are concerns that have allowed those big runs to happen in the first place.
"We know that we have given up some big plays we know with Adrian and some backs," Seattle defensive coordinator Gus Bradley said. "It's still kind of a work in progress. That's still our No. 1 emphasis after getting the ball."
Seattle enters Sunday night's matchup against San Francisco still with the No. 2 scoring defense in the NFL - right behind the 49ers - and with the 10th ranked rushing defense.
But it was the 49ers that started Seattle down the path of struggles with its run defense. It was a mix of defensive scheme and talent that helped Gore run for 131 yards when the teams faced off in Week 7. That remains Gore's season high and the second-most yards rushing allowed by the Seahawks this season.
San Francisco found its success by catching the Seahawks with some trap runs, especially in the second half that led to big running lanes for Gore.
It was a smart move schematically as the Seahawks were unprepared. Linebacker K.J. Wright said this week he'd never seen a trap play before until the 49ers ran one.
"I was lost. I was like 'what was going on?'" Wright said.
While the trap runs caught Seattle by surprise in the first meeting, it will be how San Francisco uses mobile quarterback Colin Kaepernick that'll be new for the Seahawks this time. Kaepernick was just a spectator when the teams met in October.
Since becoming the starter five games ago, Kaepernick has rushed for 202 yards, adding another element to the 49ers offense.
The Seahawks defensive line took a hit this week when Jason Jones was placed on injured reserve with torn cartilage in his knee, but defensive tackle Alan Branch should be able to play despite an ankle injury.
While Seattle did give up 118 yards rushing last week to Buffalo in an easy win, its victories over Arizona and Chicago featured a run defense that was more like what the Seahawks got earlier in the season.
Seattle held Matt Forte to 66 yards and the Cardinals to just 43 yards rushing as a team. Those two efforts gave Bradley optimism that the run defense was heading in the right direction.
"I thought the Arizona game we played better and the Chicago game for the most part we've played pretty well," Bradley said. "There are some good backs that we have faced ... Some of those guys are going to get their yards. For us the biggest thing is for us to keep the points down so we have a chance to win."