A try and penalty late on from South African brothers Dan du Preez and Robert du Preez put Sale ahead, with back row Faf de Klerk sealing the winner to deny Harlequins.
Premiership Rugby welcomed back supporters for the first time since the coronavirus pandemic when Harlequins hosted Bath on Saturday afternoon.
English rugby's Premiership returned after five months on Friday and it was Harlequins who drew first blood, beating second-placed Sale 16-10 in a possible early indicator of how pre-lockdown form will count for little.
The Gallagher Premiership will resume on Aug. 14 and the remaining nine rounds of matches will be crammed into six weeks, before the playoffs and final on Oct. 24.
The Premiership Rugby Cup final between Sale Sharks and Harlequins has been postponed after a staff member showed symptoms of coronavirus, it was announced on Friday.
Harlequins have signed former England winger Chris Ashton on a free on Wednesday following the player's departure from Gallagher Premiership rivals Sale Sharks.
Harlequins have confirmed the signing of South Africa international Wilco Louw for the 2020-21 season.
Former England captain Chris Robshaw will leave Harlequins at the end of the season after 16 years at the club.
England prop Kyle Sinckler will leave Harlequins at the end of the season to join Bristol Bears on a two-year-deal.
Far from being simply a mad scramble, a rugby ruck has no shortage of technique and regulations around it. Oh, and some dark arts as well, of course...
Champions Saracens will play Harlequins in the first rugby match at the new Tottenham Hotspur Stadium, the Gallagher Premiership has confirmed with the release of its 2019-20 fixtures.
Experienced Fiji winger Vereniki Goneva has joined Harlequins from Newcastle Falcons, the club announced in a statement.
South Africa international Travis Ismaiel will join Premiership club Harlequins after this year's World Cup.
Saracens will host future London derby matches against Harlequins at Tottenham's new White Hart Lane stadium.
Harlequins have suspended Dave Ward for one game after the hooker was shown a yellow card for stamping on Wasps' Thomas Young at Twickenham on Saturday.
Harelquins flanker James Chisholm has been banned for three weeks by the RFU for a challenge during Saturday's 38-14 defeat at Bath.
Harlequins have confirmed the signing of Namibian captain Renaldo Bothma on a long-term deal, with the 27 year-old joining from Super Rugby's side, the Bulls.
Harlequins forward Mat Luamanu has been handed a five-week suspension by the RFU for dangerous tackling.
Harlequins battle past Exeter while Gloucester comeback against Saracens
Ahead of Round 7 of the Aviva Premiership, we bring you all the team news.
Edinburgh edged past Harlequins 36-35 in thrilling encounter in the European Challenge Cup.