The victory marks the first time Quins have won the domestic knock-out cup, in any of its various guises, since 1991.
Wing Tom Williams, number eight Tom Guest, centre Tom Casson and flanker Luke Wallace all crashed over for Quins, while fly-half Ben Botica added 12 points with two penalties and three conversions.
The defeat for Sale means they have not beaten the Londoners in any competition since a 21-17 victory in the Premiership way back in September 2010 and, despite trying hard, the difference between the two sides was clear.
The Sharks' only touchdown came in the second half when centre Johnny Leota finished off some good work to add to three Danny Cipriani penalties. But it proved nothing more than a consolation.
Quins' victory was deserved and they will now look to win the Aviva Premiership title again while they are still in with a shot at the Heineken Cup.
The Londoners made only one change, which was on the bench, from the team which beat Bath in last week's semi-final.
But Sale boss Steve Diamond was forced into to late changes when both hooker Marc Jones and centre Will Addison pulled out.
Tommy Taylor replaced Jones and Sammy Tuitupou was drafted into partner Leota in the Sharks' midfield.
Watched by their England contingent who were involved in the RBS 6 Nations defeat to Wales in Cardiff on Saturday, Quins raced out of the blocks to go 8-0 up early on.
Botica landed the first points when he kicked a 40-metre penalty on four minutes and five minutes later pressure inside the Sharks' 22 saw scrum-half Karl Dickson feed Williams to go over in the right corner.
It was the worst possible start for Sale but Quins' try sparked the Sharks into action and Cipriani grabbed their first points with a 25-metre penalty.
But the Sharks' biggest problem was of their own making - with handling errors plaguing them throughout.
Quins, on the other hand, took their chances clinically, and when they were awarded a five-metre scrum on the opposition line Guest picked-up sweetly to drive over the line.
Cipriani pulled back another three points from 20 metres but only with the help of the post to deflect it over the crossbar but that was cancelled out by Botica's second penalty just before half-time to give Quins a 12-point advantage.
It was going to be a tall order for the relegation-battling Sharks to bounce back against the reigning Premiership champions.
Cipriani booted his third penalty after the break but Quins turned up the volume and two tries in nine minutes put the Londoners in the driving seat at 32-9.
Casson's try was a great move from a line-out, where a clean take by lock Charlie Matthews sent the ball via Dickson to Botica and, as a big gap opened in the midfield, the Quins centre gratefully received the present and stormed over from 25 metres.
Then flanker Wallace found the smallest of gaps from a few metres out to sneak under the Sale cover and place the ball on the line.
Sale rang the changes in one final shot to get within sight of an elusive cup victory. Their endeavour brought a try at last when Leota finished off a neat move near the Quins posts.
The Sharks were fired-up and, with Powell and flanker James Gaskell energising their pack, they took the territorial advantage in the final quarter but it was all too late as the fans from London celebrated their victory.