The Rams trailed from the outset after quarterback Matthew Stafford threw an interception on the opening drive and the 49ers converted it into a touchdown.
With the loss, Sean McVay fell to 6-18 when trailing at halftime since he was named Rams coach in 2017.
The Rams (7-3) enter their bye week on a two-game losing streak with a multitude of problems to correct in a season rich with Super Bowl expectations.
QB breakdown: For a second consecutive game, Stafford threw back-to-back interceptions, including a pick-six, in the first quarter. Both turnovers were converted into touchdowns to give the 49ers a quick 14-0 lead.
Stafford also dealt with a multitude of uncharacteristic mistakes from his typically sure-handed targets as the offense navigated its first game without receiver Robert Woods, who is out for the season after tearing the ACL in his left knee in practice.
Through three quarters, the Rams had three drops, matching their season high, with all three drops on third down. By the fourth quarter, they were up to five drops, their most in a game since 2013.
Stafford finished 26-of-41 for 243 yards and a touchdown with two interceptions.
Four of Stafford’s seven interceptions this season have occurred in prime-time games, which is tied with Kansas City Chiefs quarterback Patrick Mahomes for the most interceptions in prime time this season. Stafford-led teams have now lost 33 straight games when trailing by 14 or more points, including three losses this season.
However, it quickly became apparent that despite boasting a plethora of talent — from Miller to three-time NFL Defensive Player of the Year Aaron Donald, former first-round pick Leonard Floyd and All Pro cornerback Jalen Ramsey — the entire defense was not prepared for the 49ers physical play as Shanahan’s game plan called to run the ball non-stop before receiver Deebo Samuel continued his seasons-long destruction of his division foe, gaining 133 all-purpose yards. The 49ers finished with 156 rushing yards, the second-most allowed by the Rams this season.
The 49ers became the first team since the 2018 Indianapolis Colts to open a game with two 90-yard touchdown drives and, with inability of the Rams defense to get off the field, the 49ers dominated the time of possession, 39:03 to 20:57.
Beckham watch: Odell Beckham Jr. agreed to terms on a free-agent deal with the Rams on Thursday and four days later, the three-time Pro Bowl receiver was in the starting lineup. Stafford’s first pass of the game went to Beckham for a 5-yard completion, but three plays later, the novelty of their relationship was apparent as Stafford bought time to target Beckham downfield, only for Beckham to break off the route causing Stafford’s throw to be picked off in double coverage by safety Jimmie Ward. Beckham was targeted three times and caught two passes for 18 yards.