The game was fairly even at the interval, with both teams having scored two tries - Rory Hutchinson and Ryan Olowofela dotting down for Saints.
But Quins twice cut through Saints in the formative stages of the second half, with Chris Robshaw and Chris Ashton both scoring to put Quins 30-14 up.
Saints, who have now lost three of their four matches since the return of Premiership action, tried to issue a riposte, but they only had a James Grayson penalty to show for their second-half efforts.
Chris Boyd's side are still four points off fourth, but with Bath and Wasps playing each other on Monday, that gap will grow ahead of next Friday, when Saints host Exeter Chiefs.
The black, green and gold had won on their previous visit to The Stoop, beating London Irish just eight days earlier, and they got off to a flying start against Quins.
Saints produced a superb launch play five minutes in, allowing Grayson and Matt Procter to combine to release Hutchinson for a superb scything score.
Grayson added the extras, but Quins were keen to respond and after being repelled for a long period, they eventually won a penalty, which Marcus Smith landed to cut the gap to four points.
Saints had a great chance to put the squeeze on almost immediately, but Grayson missed a simple kick to the corner and Alex Mitchell then failed with his own effort, squandering field position.
Olowofela tried to relieve some pressure in the Saints 22 but Quins won a penalty at the breakdown and used it brilliantly, with Mike Brown taking a quick tap and Alex Dombrandt offloading cleverly in the build-up to a score in the left corner for Nathan Earle.
Smith landed the tricky conversion to make it 10-7 to the hosts, but Saints responded superbly, kicking a couple of penalties to the corner and putting the pressure on through their forwards.
Quins were forced to crack as Grayson sent a fantastic flat pass out to the right, where Olowofela was waiting to score his first Saints try.
Grayson did well to add the extras from out wide, giving his side a 14-10 lead on the half-hour mark.
But Saints were still making basic errors and after Mitchell kicked the ball straight out, Quins won a lineout penalty, which went to the corner.
A big drive from the home pack gave hooker Scott Baldwin a score, but Smith hit the post with the conversion.
He soon made amends though, slotting the final kick of the half to add another three points to his team's tally.
And Quins were first on the board in the second half as Smith breezed past Danny Hobbs-Awoyemi before Mitchell made the tackle, but it wasn't enough as the ball went wide to Robshaw, who scored in the corner.
Smith missed the conversion but Quins led by nine points and Saints were really struggling to get any momentum against a fired-up home side.
And it wasn't long before Quins opened Saints up again as Mike Brown made a break from inside his own 22 and a slick, untouched move resulted in the traditional 'Ash Splash' from Ashton.
Smith added the extras to the bonus-point score and Saints were 16 points down after a horrible opening 10 minutes after the break.
Saints almost responded with a superb score, but Olowofela's inside pass from Grayson's lovely crossfield kick was knocked on by Tom Collins.
Grayson missed touch again before landing a penalty that reduced the deficit to 13 points.
Saints introduced David Ribbans, Teimana Harrison and Taqele Naiyaravoro with 20 minutes to go as they sought to produce a late fightback.
But there was still no real momentum and Smith missed the chance to restore Quins' 17-point advantage as he failed with a penalty.
It didn't matter though, as Saints continued to huff and puff without any reward, being forced to ensure more disappointment at the final whistle.
Harlequins: Brown; Ashton, Marchant, Lasike (Lang 57), Earle (Morris 60); Smith, Care (Steele 70); Marler (Garcia Botta 70), Baldwin (Gray 70), Kerrod; Lewies (Lamb 79), Symons; Robshaw (c) (Chisholm 57), Evans, Dombrandt.
Saints: Furbank; Olowofela (Naiyaravoro 60), Procter, Hutchinson, Collins (Dingwall 68); Grayson, Mitchell (Taylor 65); Hobbs-Awoyemi (Auterac 62), Haywood (Marshall 65), Painter (Hill 50); Moon (Ribbans 60), Isiekwe; Gibson, Ludlam (c), Adendorff (Harrison 60).
Referee: Craig Maxwell-Keys