Eddie Jones' men have swept all before them in the competition since the Australian took over at the start of 2016, but found the buoyant hosts too hot to handle in the first half.
Huw Jones scored two tries and Sean Maitland another, leaving England with it all to do.
Owen Farrell, who scored all their points, grabbed a try but a full comeback never materialised.
"Congrats to Scotland, they were too good for us. We weren't in the game for the first 40. Scotland played well, full marks to Scotland. We knew what we were going to get but we didn't meet the challenge.
"They deserved their victory and I'm sure they'll have a great night."
Man of the match, Scotland’s Finn Russell was delighted - particularly in the wake of criticism of his performances in the first two games.
"It's amazing," he said. "It's been a tough couple of weeks. I kept smiling to matter what. We turned it on today, had a gameplan and executed it well."
Additional reporting by the Press Association.