I'm going with the Week 4 1999 season dismantling of SF 42-20 ending the 17 game losing streak to them
Definitely mine, and its significance cannot be overstated. It was a huge fork in the road for both teams and set the tone for the remainder of their respective seasons, if not longer.
For the Rams, that was a mental breakthrough they needed to become the Super Bowl team they were by season's end. While the Rams were definitely a better team coming in, it was still a huge test for them because they had the mental weight of 17 straight losses to those fuckers hanging over their head. Not only did they pass the test, but they absolutely fucking crushed it with a dominating win that left no doubt at all that there was a new sheriff in town and that the 9ers reign as lords of the NFC West was truly over with. The Rams confidence just soared after that game and carried them all the way to their first Lombardi.
For the 9ers, it sent their season into a tailspin. They came into the game 3-1; they finished the season 4-12. Only one lousy win for those filthy cocksuckers after that game. A bully in the NFL for so long, everybody started beating up on them, and watching their losses pile up along side the Rams wins that year was just fucking glorious, making the season all that more special. In crushing them on that beautiful October day, the Rams absolutely destroyed the 9ers confidence. That aura that the 9ers had as a winning team throughout the 80's and 90's? Gone, completely (and it's never really returned, even when those shitheels have been good). The Rams decisively and finally beat that shit out of the 9ers that day.
Just a truly wonderous day in Rams franchise history, and IMO, their most consequential regular season win ever.
Honorable Mention to the absolute ass-whipping the Rams laid on the Shithawks in Seattle in 2017. That was pretty big because it was the Rams franchise, after 12 years of The Great Suck, decisively announcing to the NFL "we're back." Gurley was just un-fucking-stoppable that game, even when they knew he was getting the ball. The defense absolutely tormented and toyed with Russell Wilson like a cat playing with a wounded bird. And Pharoah Cooper just destroyed their STs on punt returns that day. Favorite play? Gurley taking it to the house from 57 yards out on 3rd and 20. Already leading 27-0 just before halftime, and just trying to kill some clock before heading to the locker room, we added insult to injury to go up 34-0. Fantastic day to be a Rams fan.