Ollie Sleightholme scored his second try in as many Premiership appearances for Saints, but they were beaten 18-13 at Sale Sharks on Saturday afternoon.
James Grayson, who had endured a difficult day with the boot, missing two conversions and a penalty, did salvage a losing bonus point with a penalty two minutes from time.
But Sale just had enough to seal the victory, lifting themselves off the bottom of the Gallagher Premiership table in the process.
Cobus Reinach had got Saints off to the slickest of starts, scoring after some fine work from Andrew Kellaway.
But Sale recovered well and Denny Solomona's score, allied with a conversion from Rob Du Preez put them 7-5 up at the break.
Du Preez added a penalty in the second period before Sleightholme's score got Saints level.
But Grayson missed the chance to get his team ahead with a tricky touchline conversion, and Solomona's try and a Du Preez penalty sealed it for Sale.
Grayson did get on the scoreboard with a penalty late on, but it wasn't enough for Saints.
Chris Boyd's side had gone into the game full of confidence after a barnstorming 36-17 success against Wasps at Franklin's Gardens seven days earlier.
And they displayed that belief as Kellaway did some superb work, breaking the line before combining with Taqele Naiyaravoro to set up the onrushing Reinach for the score.
Grayson missed the conversion but his side were ahead with little more than a minute on the clock, leaving the home fans at the sparsely-populated AJ Bell Stadium stunned.
There was a lengthy delay soon after as Sale tighthead prop Will-Griff John was stretchered off and when play resumed, the home side were knocking loudly on the Saints door.
After lively wing Arron Reed was denied a fine try, the Sharks put the pressure on once again and Naiyaravoro's failure to pinch a pass left space for Solomona to score.
Du Preez converted impressively from the touchline and Sale led 7-5 with nine minutes played.
Saints tried to respond immediately, going for the corner twice, but Sale stood tall, winning a penalty and eventually managing to clear their lines.
When they got possession at the other end, the Sharks were desperately trying to inject some tempo into their play, but Saints' line speed was excellent, with Fraser Dingwall and Luther Burrell making big, important hits.
Solomona did find his way over the line again five minutes before the break, but his effort was ruled out for blocking in the build-up, with Jono Ross having impeded Teimana Harrison.
Saints were dealt an injury blow as they lost George Furbank, with Sleightholme introduced on the wing and Kellaway switching to full-back.
But the away side had the edge against Dorian West's Sale pack, with Paul Hill dominating, and Saints won a penalty on the stroke of half-time, which Grayson sent just wide.
Sale tried to step things up at the start of the second half, but they were thwarted by a crucial Sleightholme turnover.
But the Sharks were showing more bite now and after a scything run from Reed, they won a penalty, which Du Preez landed to make it 10-5.
Saints eventually got some territory 15 minutes into the second period and after Sale failed to deal with an attack out wide, Sleightholme popped up to score.
Grayson was having a difficult day with the boot though, and he missed the conversion to leave the scores level.
But they weren't level for long as Saints were also caught short on their left side and Solomona found space to score his second.
Du Preez failed with the touchline conversion but Sale kept coming and Naiyaravoro had to do some good last-ditch defensive work as he dragged Reed into touch.
But Sale got the points they needed to give themselves real breathing space as Kellaway was penalised for a high tackle and Du Preez notched the penalty.
That put the Sharks 18-10 up with just five minutes to go, but Grayson cut the gap to five points with a penalty 90 seconds from time.
Saints had time to mount one last attack but when Naiyaravoro failed to make the pass inside his own half, referee JP Doyle blew the final whistle to confirm the Sale success.
Sale Sharks: S James; Solomona, O’Connor, James, Reed (Odogwu 75); R Du Preez, De Klerk (Cliff 75); Harrison, Webber, John (Jones 4); Beaumont, Phillips (Evans 63), Ross (c), B Curry, Du Preez.
Saints: Furbank (Sleightholme 36); Kellaway, Dingwall, Burrell, Naiyaravoro; Grayson, Reinach (Mitchell 73); Waller (c) (van Wyk 60), Fish (Marshall 60), Hill (Franks 60); Ratuniyarawa, Moon (Barrow 73); Wood (Gibson 60), Ludlam, Harrison (Eadie 70).
Referee: JP Doyle