San Francisco's trip to SoFi Stadium marks a critical game for these NFC West rivals, who have both struggled to produce their best this season.
After a bye week, the defending Super Bowl champion Rams are 3-3, while the 49ers are coming off back-to-back losses, which have dropped them to 3-4.
However, the 49ers have plenty of reason for confidence of getting back on track before their bye week against an opponent they defeated 24-9 in Week 4.
That victory made it seven straight regular-season wins over the Rams for the Niners, their second-longest streak against Los Angeles all-time (17 straight from December 1990 – December 1998).
But the 49ers will not have happy memories from their previous visit to Los Angeles, the Rams having prevailed 20-17 in last season's NFC Championship Game to book their place in the Super Bowl.
Wide receiver Deebo Samuel played a critical role in that game and has been a key feature in the 49ers' success against the Rams.
Samuel has accounted for seven regular-season touchdowns in his career against the Rams (three receiving, three rushing, one passing) but will be unavailable for San Francisco this weekend due to a hamstring injury.
The loss of the best running wide receiver in the NFL may see greater onus placed on arguably the best receiving running back, with McCaffrey sure to be an integral part of the gameplan after the 49ers traded four draft picks to acquire him from the Carolina Panthers.
McCaffrey averaged 6.2 yards on his 10 touches in his debut against the Kansas City Chiefs and, though the 49ers will look for him to boost a run game that has a disappointing success rate of 33.7 per cent through seven weeks, the absence of Samuel and their underwhelming ground game could see San Francisco feature the former Panther heavily in the passing game.
San Francisco's 44-23 loss to the Chiefs last week marked the first time they have lost back-to-back games by at least 14 points since Weeks 9-10, 2020. They followed those games up with a 23-20 win against the Rams in Los Angeles.
The 49ers will look for a defensive upturn after their struggles against Kansas City, though defensive coordinator DeMeco Ryans' group is still battling injuries in the front seven.
Holding the Rams in check will be critical to San Francisco's hopes of overcoming their absences. Los Angeles have scored at least 20 points in all three of their wins this season and 10 or fewer points in all three losses.
Rams quarterback Matthew Stafford's record against the 49ers should also offer optimism to Kyle Shanahan's team. Stafford is 1-6 in his regular-season career against the 49ers, his worst record against any NFC opponent.
Stafford has thrown four touchdown passes and five interceptions in his three games against them since joining the Rams, losing each one. Whether he improves on Sunday is likely to have a huge say in which teams emerge from the NFC West.