Kyren Williams added two touchdown runs for the Rams (7-2), who avenged a home loss in overtime to the 49ers (6-4) in Week 5 to remain in a tie for first with Seattle in the NFC West.
Stafford's 13 touchdown passes the past three games are the most in franchise history and he became the first player in NFL history with at least four TD passes and no interceptions in three consecutive games.
San Francisco has lost its top two defensive players for the season with Nick Bosa and Fred Warner both out and last week lost first-round rookie Mykel Williams to a season-ending knee injury.
The Rams scored TDs on their first three possessions for the first time in five years to take a 21-0 lead early in the second quarter behind two TD passes from Stafford.
Mac Jones connected on a 6-yard TD pass to Jennings late in the half to make it 21-7.
Jones finished 33 for 39 for 319 yards with three TDs and one interception, falling to 5-3 in place of the injured Brock Purdy.
49ers: Purdy was inactive for the sixth straight game with a toe injury. He has practiced on a limited basis for three weeks but hasn't been active for a game since Week 4.
Up next
49ers: Visit Arizona on Sunday.
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