Owen Farrell kicked 14 points and David Strettle scored against his old club as Saracens raced into a match-winning 19-3 lead after just 24 minutes.
Harlequins attempted a comeback and prop Joe Marler, whose pass had been intercepted by Strettle, scored in a dominant second-half performance from the hosts.
Saracens did not score another point but they defended resolutely to seal the victory in front of 82,000 supporters and close the gap on league leaders Harlequins to five points.
The extraordinary crowd was a world record for a regular-season club fixture, beating the 79,842 that watched Stade Francais v Clermont Auvergne in the French Top 14.
It was also the biggest crowd ever to watch a Premiership match, including any of the Grand Finals staged at Twickenham.
Fireworks exploded from the roof of the national stadium as Harlequins ran out. The intensity at ground level was fierce but the lack of pyrotechnics an indication in itself of Saracens' intent to be party-poopers.
Saracens can play attacking rugby at pace, as the Ospreys discovered to their cost in their Heineken Cup showdown at Wembley.
But this was no exhibition game. They were not obliged to play to the galleries just to make this a festive feast of running rugby.
Mark McCall's men countered Harlequins' natural adventure by slowing the game down and drawing penalties, which Farrell converted at will.
The 20-year-old England prospect slotted three inside the first 13 minutes to but Saracens in the box seat as Harlequins struggled to match their intensity at the breakdown.
Harlequins showed an indication of their attacking promise when Nick Easter pounced on an overthrown lineout allowing Maurie Fa'avasalu, Matt Hopper and Seb Stegmann to launch a counter-attack.
Saracens scrambled well but conceded a penalty and, after the first of many shoving matches during a feisty half, Nick Evans kicked Harlequins onto the scoreboard.
It was a brief respite. Harlequins compounded the situation when Marler's soft pass inside his own 22, intended for Easter, was picked off by Strettle who cruised over for the try.
Farrell succeeded with the conversion and then slotted a fourth penalty after excellent work from Andy Saull, who was making his 100th Saracens appearance in place of the injured Jacques Burger.
Harlequins attempted a quick lineout from Peter Stringer's clearance to touch but Saull had followed the kick up well, executed a brilliant turnover and Strettle made an elusive break up field. Although the Saracens' move was halted by some solid defence, Harlequins then knocked on and conceded a penalty at the subsequent scrum.
Farrell made no mistake and Saracens were in an impregnable position.
In the face of a side playing no-risk rugby and tackling themselves to a standstill, Harlequins' hopes of getting back into the game were bleak indeed as the interval approached.
The sight of Evans skewing an attempted kick-pass backwards just about summed up their predicament but Harlequins lack nothing in the spirit department, as Toulouse discovered.
They finished the half on the front foot, with Danny Care almost finding a way through before Stringer was penalised for killing the ball.
Evans went for touch but Saracens' defence remained rock-solid.
They repelled Easter and Ugo Monye before Alex Goode's shuddering tackle on Hopper forced the turnover.
Harlequins kept hammering away but found no chink in the Saracens armour and eventually had to settle for a second Evans penalty to go in 19-6 down.
Harlequins had to up the intensity after the interval and they did so, winning quick ball and breaking the gainline with consistency. Saracens did not score a point in the second half.
Tom Williams, Hopper and Monye all threatened before Harlequins' forwards cranked up the pressure and Marler atoned for his first-half mistake with his third Premiership try.
Evans missed the conversion but Harlequins kept their foot on the jugular, dominating over 70% of second-half possession in search of the converted try that would draw them level.
When Easter crashed through a hole in the defence and into the Saracens 22, they appeared to have found it but Fa'asavalu could not hold onto the offload and the chance went begging.
Saracens had made more than three times as many tackles as Harlequins but they continued to make them, defending valiantly to seal the win.
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