Former England international Nick Easter touched down for one of Harlequins' three tries as they extended their lead at the top of the table.
Cameron Shepherd's try took Sale into an early lead, but Quins controlled the rest of the half with Tom Williams touching down and Ben Botica adding eight points with the boot.
Botica continued his fine form in the second period with another penalty before converted scores from Easter and Charlie Matthews sealed a fine victory, their 12th in 13 games.
Richie Vernon and Sam Tuitupou scored consolation efforts in the last few minutes for Sale, but the result means they still reside at the bottom of the league.
After securing four wins in succession, the Sharks were handed a further boost when Rob Miller and Dan Braid put pen to paper on new deals.
Although Miller sat out this game, his replacement, former Australia international Shepherd, got the Sharks off to the perfect start.
Just two minutes had elapsed when Quins were turned over in the contact area. Will Cliff then fed Henry Thomas and good hands from Tuitupou and Mark Cueto sent the full-back away.
Danny Cipriani converted impressively from a difficult angle and the league's bottom club led 7-0 but the visitors, in typical fashion, went on the attack.
Jordan Turner-Hall made indents in the Sale defence and, after they infringed at the breakdown, Botica slotted the resultant opportunity.
Despite their fine opening, it was the London-based outfit that began to dominate. Ill discipline at the tackle area was proving costly and Harlequins' Kiwi stand-off added a second from the tee to reduce the arrears further.
Another penalty then forced referee Martin Fox to send Tuitupou to the sin-bin and the away side profited when Williams touched down.
Karl Dickson took advantage of the space left by Cueto, who was lying injured on the ground, and his surging run was finished by the right winger.
Botica was successful with an easy conversion as Quins deservedly led 13-7 at the interval.
The second half continued with the defending Premiership champions controlling proceedings and their fly-half took them nine points clear after another Sharks' indiscretion.
Sale had barely touched the ball throughout the match but a penalty chance allowed them an opportunity to get back into the encounter. However, Cipriani was off target with the attempt.
Harlequins' back-row Maurie Fa'asavalu then received a yellow card for punching Marc Jones, but it was one of Europe's outstanding outfits that were by far the more inventive.
Dickson in particular was causing problems around the fringes and his piece of quick thinking nearly resulted in another score.
Although the hosts initially held out, a lineout drive saw Easter touch down, Botica converting, to take the score to 23-7.
Further pressure on the home team's line then led to Matthews going over as they crumbled under Quins' sheer power.
Vernon and Tuitupou crossed late on as the home side rallied, but it was too little too late.
An astonishing finish at Kingsholm saw Gloucester record a remarkable 29-23 win over Worcester with a late penalty try in the night's other Premiership match.
With 20 seconds remaining, Jonny May burst away on the left flank and reached the visitors' 22 before attempting to step inside full-back Errie Claasens, who felled the flying wing with a trip.
On the advice of the TMO Claasens was sent off and Gloucester were awarded a penalty try, converted by Rob Cook, which broke Worcester hearts as they seemed set for a shock win which would have allayed their relegation fears.
Gloucester recalled centre Henry Trinder and prop Dan Murphy to the starting line-up with Mike Tindall being a very late withdrawal to be replaced by Tim Molenaar.
Worcester made four changes following last week's defeat by Northampton with wing Josh Drauniniu dropping to the bench. Chris Pennell replaced Drauniniu and there were also recalls for No 8 Blair Cowan, centre Josh Matavesi, and prop Matt Mullan.
Worcester had the first chance for points but Andy Goode's long-range penalty attempt rebounded back off the crossbar.
Cook had a similar opportunity but he made no mistake to give the hosts a seventh minute lead.
Moments later, Cook was again on target with another penalty before the increasingly dominant Gloucester almost scored the opening try.
A clever chip ahead from Trinder saw May just fail to win the touchdown as the ball ran into the in-goal area.
A Goode penalty put the Warriors on the scoreboard to make it 6-3 to Gloucester at the end of the first quarter before Cook had a chance to restore the six-point lead but he badly mishit his penalty attempt.
Gloucester continued to control both possession and territory but with the award of frequent penalties, they could not take advantage as play was constantly disrupted.
Eventually the patience of referee, David Rose, was exhausted and he sent Worcester flanker, Sam Betty, to the bin for a dangerous challenge on Charlie Sharples.
With three minutes to go before half-time, amazingly Worcester took the lead with a splendid solo effort from Matavesi, who skipped past attempted tackles from Trinder and Darren Dawidiuk to run 22 metres for the try which Goode converted.
Stung by the reverse, Gloucester's reply was immediate, producing a counter-attack from inside their own 22 which ended with May sending Trinder in for the try which Cook converted to give the home side a 13-10 interval lead.
Betty returned from the bin but within seconds of the restart, Worcester infringed, with Mullan not releasing allowing Cook to kick his third penalty.
More ill-discipline from the Warriors, this time a late tackle from Jonny Arr on Ryan Mills, resulted in Mills stepping up to kick a penalty to put Gloucester further ahead.
Goode kicked his second for Worcester as the visitors continued to battle hard to frustrate Gloucester.
Surprisingly Goode elected not to kick another penalty in favour of a speculative cross-field kick and the chance to further reduce the arrears was lost.
Goode fired wide with another penalty but Warriors regained the lead when he converted a try from Alex Grove, who had raced 20 metres after intercepting a lazy pass from Molenaar.
With 10 minutes remaining, Cook put Gloucester back in front with a simple penalty but home prop, Rupert Harden, was penalised for not rolling away for a Gray penalty before the dramatic finish ruined Worcester's hopes.