England internationals Danny Care and Mike Brown went over in the first half as Quins established a 15-3 advantage at the interval, with Nick Evans adding a conversion and a penalty.
Tommy Bell responded for Sale with a penalty before two second half Evans' three-pointers extended the visitors' advantage.
Will Addison crossed for the Sharks to give them hope, but a further penalty sealed the win for Harlequins and a home semi-final with Northampton in the play-offs.
Despite it being their final game before moving to the Salford City Stadium and Heineken Cup rugby not technically assured, Sale decided to go with a weakened outfit to fulfil the RFU's English-qualified agreement and garner £80,000 in the process.
However, it was the hosts who started the brighter. In their own half, the Sharks attacked the blindside through Luther Burrell whose exquisite off-load put Mark Cueto in space.
Cueto's grubber through was collected by Addison who touched down, but the try was disallowed for a push on Quins' full-back Brown.
Although the home side played with verve early on, their inexperienced set-piece struggled. The pressure told and they were duly punished at the scrum, but Evans failed to convert the resultant penalty opportunity.
It was Sale who were next to attack as once again they ran from deep. Good interplay between Dave Seymour and Lee Imiolek sent Tom Brady clear before the winger was held up by some impressive visiting defence.
And the failure to take their chances cost them dear. In the 22nd minute, powerful surges from the visitors' forwards got them to inches of the line. Care then showed his athleticism to jump over the ruck and touch down.
Evans slotted the simple conversion as Quins took a 7-0 advantage against the run of play.
But it was the lift they needed to establish their authority, and they nearly went over seconds later. After George Lowe had burst through the middle, the ball was recycled out to Brown who was shepherded into touch.
Sale finally got on the board through the boot of youngster Bell before Evans restored the visitors' seven-point advantage.
However, it was Quins who continued to have the better of the play in the latter stages of the opening period.
And they scored their second try when a wonderful flat pass sent Brown through a gap. The England international then evaded Rob Miller's weak tackle to cross to whitewash.
The Twickenham Stoop-based outfit started the second half as they finished the first, continually challenging the Sharks' game-line.
Successive Evans' penalties took the advantage out to 21-3 before Nick Easter was sin-binned for Harlequins.
That seemed to spur the hosts on as Addison made a late case for 'try of the season' with an outstanding individual score.
Taking the ball in midfield, the centre weaved past two defenders to go over from 50 metres.
Bell added the extras and Sale began to dominate possession, however, excellent Quins' defence and minor errors stopped them from scoring any further tries.
And Evans secured the victory with a three-pointer eight minutes from time.
Despite the defeat, the Sharks will be playing Heineken Cup rugby next season after Bath's loss to Leicester Tigers.
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