Saints scored five second-half tries but their Champions Cup hopes were extinguished during a dreadful first 60 minutes at Franklin's Gardens on Saturday evening.
Jim Mallinder's men shipped six tries as they were beaten 43-32 by an injury-ravaged Ospreys side, who had previously only won two of their 13 games in all competitions.
Saints have now lost nine of their past 10 matches and the sparsely-populated stands told the tale on another chastening day for the club.
The green, black and gold are stranded at the bottom of Champions Cup Pool 2, having suffered three heavy defeats in as many matches.
And they must now do more soul-searching when they head to Swansea for another another clash with Ospreys next Sunday.
Saints were 43-8 down during the Northampton leg of this December Champions Cup double-header as Ospreys flew into the lead, prompting more boos at the Gardens.
Nic Groom, Rob Horne, Ahsee Tuala and Harry Mallinder did manage to provide the smallest glimmer of hope with late tries that added to Dylan Hartley's 52nd minute effort.
Ospreys were down to 13 men late on as Rob McCusker was yellow carded for his part in a brawl with Harry Mallinder, who was also sin-binned, and Hanno Dirksen was sent off for a high tackle on JP Estelles.
But a try bonus point was all Saints had to show for their efforts as they failed to complete what would have been one of the most incredible comebacks in rugby history.
Mallinder's men had gone ahead early in the game with Stephen Myler, who was an eighth-minute replacement for head injury victim Piers Francis, landing a penalty.
Ospreys' discipline in the formative stages of the game was poor and winger Jeff Hassler paid the price for his team's persistent infringements as he headed for the sin bin.
But the Welsh side were soon level as Sam Davies slotted a penalty from in front of the posts.
And Saints were struck with another blow as Myler became the second fly-half forced off with an injury, meaning Harry Mallinder was switched to 10.
It was misery upon misery for the home side and the atmosphere were even flatter after Ospreys shifted the ball right and full-back Dan Evans dotted down.
Davies kicked to rub salt in the wounds, making it 10-3 with almost half an hour played.
And it was to get worse for Saints before the break as a cutting move ended with Tom Habberfield cruising in unopposed.
Davies converted, with plenty of Saints fans heading off for early half-time refreshments, most likely to be from the bar.
Ospreys looked to have twisted the knife even more just after the break as Alun Wyn Jones picked up and ran over the whitewash.
But the skipper was denied a try for an offside in the build-up and Saints were handed a penalty.
It wasn't long before Ospreys did grab their third try though as they made the most of numbers on the left to send Hassler away for his second.
Davies again converted and he was soon adding the extras to the bonus-point score, which came from Kieron Fonotia finding yet another gap in the home rearguard.
Saints finally gave the fans who had stuck with it something to shout about as a big forward drive gave Hartley a try.
Harry Mallinder missed the conversion and Ospreys were soon celebrating again as the impressive Evans stretched out an arm to score.
Davies kicked the conversion to make it 38-8 and the torture was not yet complete as Hassler bagged his second score.
Davies missed a conversion for the first time, but he barely blinked as he picked up the tee as the extras didn't matter with his team's work seemingly more than done.
Groom did show some good determination to force his way over in the corner, but Mallinder again sent the conversion wide to leave the score at 43-13.
Saints were finally getting some joy in the opposition half and Horne was next to add his name to the scoresheet, with Mallinder's conversion cutting the gap to 23 points.
The Ospreys were now really starting to slack off and Saints were able to claim a try bonus point as a lovely move, that included a fine Harry Mallinder offload, was finished by Tuala.
Mallinder converted and suddenly there was the smallest glimmer of hope at 43-27 down with 12 minutes remaining.
Saints were now really turning up the heat and after Tuala intercepted and offloaded brilliantly to Mallinder, the youngster sprinted from halfway to score a fine try.
A brawl followed, with Mallinder and Ospreys replacement McCusker sin-binned for their part in it, meaning Saints had to hand kicking duties to Cobus Reinach.
His first act was to hit the post from the tee and the needle between the teams continued soon after as Dirksen produced a sickening high tackle on Estelles.
It earned Dirksen a red card, leaving Ospreys down to 13 men with three minutes to go.
But the Welsh side saw the game out to stop Saints securing a losing bonus point on an eventful evening at the Gardens.
Saints: Mallinder; Tuala (Reinach 71), Horne, Burrell, Foden; Francis (Myler 8 (Estelles 19)), Groom; Van Wyk (Ma'afu 53), Hartley (c) (Haywood 60), Ford-Robinson (Hill 60); Ribbans (Paterson 53), Day (Gibson 57); Lawes, Ludlam, Harrison.
Ospreys: Evans; Dirksen, Fonotia, Watkin, Hassler; S Davies, Habberfield; Smith, Baldwin, Arhip; B Davies (Beard 65), Wyn Jones (c); Lydiate (McCusker 63), Cracknell, King.
Referee: Alexandre Ruiz