Flankers Dave Seymour, James Gaskell, left-wing Rob Miller and replacement Danny Cipriani scored tries for the Sharks, who had also lost 24-3 at The Stoop last month in the Aviva Premiership.
Fly-half Nick Macleod kicked nine points for Sale, with Cipriani also converting his own try.
Opposite number Ben Botica replied with 21 points for Harlequins - a try, two conversions and four penalties in a 100 per cent kicking performance - with winger Charlie Walker grabbing their other try.
Quins struggled with their set-piece in the early stages, losing their first two line-outs and their opening scrum.
But they took the lead in the ninth minute, capitalising on a turnover on the halfway line. Right-wing Walker burst through the middle and passed out of the tackle to leave Botica a clear run to the line for a try which the fly-half converted.
Sale responded with an attacking spell which saw Quins desperately defending their line.
Allowed the advantage by referee Ian Tempest, Macleod and Gaskell, playing for the first time since breaking a bone in his foot in the pre-season match against Wasps, quickly moved the ball left to send Seymour over unchallenged. Macleod converted to level the scores at 7-7 after 18 minutes.
Harlequins twice paid for their indiscretions, first when Macleod kicked Sale into the lead with a 24th-minute penalty and again, seven minutes later, when Wallace was sin-binned for offending at a ruck.
The Sharks exploited their numerical advantage to score a second try with Macleod, hooker Tommy Taylor and centre Will Addison stretching the home defence to send Miller in for a try converted by Macleod.
Their captain's return from the sin-bin galvanised Harlequins whose late first-half pressure resulted in Botica landing a penalty with the final kick of the session before adding another four minutes into the second half.
But Sale struck again when their pack drove Gaskell over from close range to leave Macleod an easy conversion.
Quins responded four minutes later with Walker taking the final pass from Wallace to finish off a slick high-speed move, with Botica again converting.
Sale immediately introduced new signing Viliami Fihaki, the 26-year-old Tonga No.8 who only arrived on Wednesday from New Zealand provincial side North Harbour, and Cipriani.
Fihaki's debut lasted only 13 minutes before he was sin-binned for an off-the-ball challenge on Botica, which presented the fly-half with his third penalty.
But Sale wrapped up victory with Cipriani racing in for their fourth try in the left corner and striking the conversion.
Botica's fourth penalty sparked a grandstand final assault by Quins but Sale held on to their lead.
- Sports & Recreation
- Nick Macleod
- Danny Cipriani
- Ben Botica
- James Gaskell