Hounded throughout the game by the Tennessee Titans' defence, Stafford threw two critical interceptions as the Rams fell 28-16 at home.
The turning point of the game occurred early in the second quarter, when Stafford tried to throw the ball away while being pulled down by Jeffrey Simmons in the end zone.
His blind heave landed in the arms of Titans linebacker David Long, who returned it to the two-yard line and set up a Tennessee touchdown on the next play.
The Rams (7-2) got the ball back after the kick-off and Stafford took to the air again, trying to hit Robert Woods, but Titans defensive back Kevin Byard jumped it and went 24 yards for the Titans' second TD in 11 seconds.
It was the 24th time Stafford had an interception returned for a touchdown, the most of any active NFL quarterback.
"I mean, I basically spotted them 14 points," Stafford told reporters. "Can't do that in the NFL, especially against a good team like that that wants to get out in front, run the football, mix coverages, do all that kind of stuff. Just wasn't good enough early in the game.
"Turnovers really killed us and those are on me, so if I clean those up and I know I will, I've got a lot of confidence in this team to go out there and play some really good football."
Though Stafford could have made better decisions on both of those plays, Tennessee's defenders were flying around the field all game.
The Rams had surrendered an NFL-low eight sacks through the first eight games, but the Titans (7-2) brought down Stafford five times on Sunday.
"Those guys played fantastic," Titans head coach Mike Vrabel said of his defence. "It was fun to watch them play.
"We really think that group is playing with a lot of confidence right now. They would be able to come in here and play the way they did and hold them to field goals, and we played great in red zone."
Tennessee twice forced the Rams to settle for field goals in the red zone and did not surrender a touchdown until Stafford threw a three-yard pass to Sony Michel with 24 seconds to play in the game.
It all added up to a winning formula for the Titans even as they managed just 194 yards of total offence while playing without their injured star Derrick Henry.
"Those guys played some great ball defensively. It made up for our lack of offence," said veteran running back Adrian Peterson, who signed with Tennessee this week and scored his 125th career touchdown.
"You hear all this talk about the Rams' defence. What about the Titans' defence? Those guys came out and played outstanding."
Vrabel saw his team crushed 35-10 at Lincoln Financial Field as the Eagles improved to 11-1 in an outstanding season.
Former Titans wide receiver A.J. Brown, traded to the Eagles on draft day this year, had eight catches for 119 yards and two touchdowns against his former team in a superb display.
For Tennessee, the blowout loss comes on the heels of a narrow loss to the Cincinnati Bengals, dropping them to 7-5.
The Titans are almost certainly going to win a poor AFC South division, but these back-to-back defeats raise substantial questions about Tennessee's ability to contend for postseason success.
"I think we are at a crossroads," Vrabel said. "I told the team I think we are at a crossroads at kind of how we want to continue down this season.
"We can't point fingers. We have to assume that each and every one of us didn't do a good enough job because we didn't.
"We have to come to work with greater energy and greater resolve to prepare to win a football game against a division opponent.
"It sucks losing, it sucks getting beat the way we did but we have to make a decision, how much are we willing to invest and trust in what the coaches are doing, trust in what each of the players are doing. I think it’s a critical time for us."
The Titans will be favoured to get back on track next week when they host the Jacksonville Jaguars on Sunday.
Vrabel told reporters via video conference that he woke up on Sunday with a sore throat and went to the team's facility for a coronavirus test, which came back positive. A second test also was positive.
The 46-year-old Vrabel has previously said he is vaccinated.
"As of now, I’ll be in quarantine, following the protocols and trying to do my best to help the football team while I am [home]," he told reporters.
"I am very confident in our football team, our coaching staff, our organization, that no matter what the situation is, we’ll handle it."
The Titans spent several days last week in Tampa holding joint practices with the Buccaneers ahead of Saturday's pre-season game, which Tennessee won 34-3.
ESPN reported the Buccaneers were waiting on contact tracing, along with the Titans.
Vrabel told reporters he was not aware of any other positive tests among the Titans on Sunday.
Tennessee was the first NFL team to experience a major COVID-19 outbreak last season, with 13 players and 11 staff members testing positive over several weeks.
Those issues resulted in two games being rescheduled.
The Titans' final pre-season game is set for Saturday at home against the Chicago Bears.
They will host the Arizona Cardinals on September 12 to open the regular season.
The game was postponed to Tuesday following a spate of positive coronavirus tests for the Titans, which led to their training facility being closed.
It meant Vrabel's team had just three practices in 16 days, but that did not stop them dominating at LP Field, where Derrick Henry rushed for two touchdowns and Ryan Tannehill completed 21 of 28 passes for 195 yards and three TDs.
The display filled Vrabel with pride and confidence that his men can overcome any difficulties to prevail.
"I'm never going to question this football team. I'm never going to question the effort," Vrabel said, per ESPN.
"I'm never going to go into a game questioning how we're going to do. I expect us to win and play with great effort.
"You don't all of a sudden galvanise when things are bad. I think that's a testament to the players and what we've tried to build here.
"You don't always say, 'Oh, there's a s***-storm. We better galvanise.' You stay tight throughout, and you hope that the fundamentals and your core beliefs and core values take over when things get difficult."
The clash was tied after the opening quarter, in which Isaiah McKenzie scored after Tannehill and A.J. Brown connected on a 16-yard pass.
Henry surged over to reclaim the lead for the Titans in the second quarter and Tannehill's 10-yard run saw them into a 21-10 half-time advantage.
Quarterback Josh Allen, who went 26 of 41 for 263 yards with two TDs for the Bills, threw one of his two interceptions to Malcolm Butler in the third quarter and the Titans capitalised through a Jonnu Smith TD.
Given plenty of time, Allen found T.J. Yeldon with a 22-yard pass into the end zone in the fourth quarter, but Henry and Smith ensured the Titans pulled away for a comprehensive victory.
The Titans are top of the AFC South, while the Bills (4-1) remain in first place in the AFC East.
The Titans were 10-0 down at half-time, but touchdowns from D'Onta Freeman and the returning A.J. Brown put them in front.
Niners quarterback Jimmy Garoppolo, who completed 26 of 35 passes for 322 yards, threw his only TD pass for Brandon Aiyuk to level the game in the fourth quarter.
Randy Bullock had the final say, though, making no mistake with a field goal with four seconds left, ensuring Tennessee (10-5) can win the AFC South if the Arizona Cardinals beat the Indianapolis Colts on Sunday.
Titans head coach Vrabel said: "The funeral for the Titans was supposed to be yesterday or today. We're not dead yet."
Brown was making his first appearance since Week 11 after recovering from a chest injury and certainly made his presence felt.
The wide receiver took a career-high 11 catches for 145 yards and was able to celebrate a long-awaited touchdown.
Vrabel said of Brown: "We understand how important he is to our football team. Love him as a person. Glad to have him back."
He added: "A.J''s fantastic. We expect those things from A.J."
Ryan Tannehill threw 22 of 29 passes for 209 yards while Brown finished with 11 receptions for 145 yards.
Defeat for the 49ers (8-7) ensured the Dallas Cowboys (10-4) will feature in the playoffs for the first time in three years.
Dallas (10-4) clinched its first playoff berth in three years Thursday, thanks to the Tennessee Titans' 20-17 victory over the San Francisco 49ers.
