While victory for 2022 Super Bowl title favourites was not a surprise, the size of the scoreline certainly raised a few eyebrows.
The 21-point margin marked the second-largest defeat in a season opener for a reigning champion.
Speaking after the game, Rams head coach Sean McVay told NFL.com: "We weren't ready to go, I take a lot of pride in that, and that's on me.
"I gotta do better, there were a lot of decisions that I made that I felt like didn't put our players in good enough spots.
"This was a humbling experience, but we're going to stay connected, we're going to look inward, we're going to do a better job of moving forward, but you give credit to the Bills, and then we've got to understand that we've got to have that mindset and mentality to be able to move forward accordingly."
Bill quarterback Josh Allen enjoyed a particularly good evening as his side racked up 413 yards and scored 21 unanswered second-half points.
McVay, whose team mustered a mere 243 yards, added: "Yeah, we just didn't get in much of a rhythm tonight, so it was tough to get anything.
"I'd like to get Allen more involved, I'd like to get a lot more guys involved. Overall, it was just a tough night for us."
McVay made sure to put the responsibility of the result on his own shoulders, saying: "The bottom line is, I didn't do a good enough job at getting us ready to go to our capabilities.
"I have total belief and confidence in what we can do moving forward, whether we won tonight or whether we had a humbling experience like this, we've got 16 games guaranteed left.
"We're going to dust ourselves off, we're going to look ourselves in the mirror, we're going to be accountable to the things that we all can do better within the framework of our roles, and we're going to move forward the right way. And that's all I know how to do."