Sean Maitland scored a try on his Scotland debut to give the visitors hope, but the hosts took charge of the match with tries from Chris Ashton, Billy Twelvetrees - on his England debut - Geoff Parling and Danny Care, with Stuart Hogg scoring a second try that was scant consolation for the Scots.
The home side never looked in danger, and while the Scots produced decent rugby at times the penalty count against them made sure that they never had any chance of staying in the game.
England will head to Dublin next week full of confidence after the victory, while Scotland will now have to wait another two years for a chance to end a barren spell at Twickenham which stretches back to 1983.
Stuart Lancaster's men started the match keen to dominate, no doubt still full of confidence after their record win over New Zealand at the end of 2012, and within three minutes Owen Farrell landed a penalty to put them ahead.
Eight minutes later the form book was turned upside down, however asHogg collected a routine punt upfield, and made an outstanding break up the right flank which almost took him to the line. Though he was hauled down he recycled well and Maitland was on hand to pick up and score in the corner less than 11 minutes into his Scotland debut.
With the conversion from the right touchline proving too much for Greig Laidlaw, England were able to go 6-5 in front almost immediately as a penalty straight from the restart allowed Farrell to land a kick from just outside the 22.
And yet another sloppy mistake - a terrible pass by David Denton that was a good four feet over Ruaridh Jackson's head - put pressure on the Scotland defence and saw them concede another penalty. Farrell stroked it over again, though Laidlaw was able to cancel it out immediately after Tom Youngs flew in over the top at the breakdown immediately upon the game restarting.
There was no element of luck as England finally scored a try with Tom Wood making a superb charging run into the Scotland 22 to break open the visitors' defence and Ashton scooping up to score.
Farrell added the extras, and made it five out of five to put England 19-8 ahead just before half-time as Johnnie Beattie was penalised for an innocuous but undeniably high tackle.
Beattie made up for it in style, however as with half-time beckoning he made a storming run from the restart, putting England on the back foot and prompting Wood to give away a penalty almost in front of the posts.
Laidlaw knocked it over to trim the deficit to eight points at half-time and give Scotland hope in the second half.
Those hopes were dashed within three minutes of the restart. England pushed forward immediately, recycling the ball a dozen times in the Scotland 22 to put huge pressure on and earning the inevitable try as Alex Goode popped the ball up from a ruck to Twelvetrees, running in fast at an angle to score a try on his debut.
Foul play by Tom Youngs robbed Joe Launchbury of a try 10 minutes later, but within two minutes the visitors had been opened up again. Ben Youngs cut the defence open with a blistering run before offloading to Farrell, whose long pass to Parling let the second-row run in his first international try.
Scotland briefly sparked hope of an unlikely fightback as Maitland's kick-through let Hogg in to score a well-deserved try.
But they could get no closer, and Care added further insult as he dived in under the posts with the clock in the red to complete a devastating victory for the hosts.