London Irish stunned Northampton with two tries in the last 10 minutes as Saints missed the chance to go back above Exeter on top of the Premiership.
Hooker Dave Porecki's pass set up the first for Franco Van der Merwe before Porecki scored a charge-down try.
Saints had led 13-8 at the break after Cobus Reinach's try cancelled out Ollie Hassell-Collins' opener for the Exiles.
But the visitors cashed in on a match-turning red card for home lock Api Ratuniyarawa in the 50th minute.
That was Saints' second red card in successive Premiership games after Tom Collins' dismissal in the last-gasp 35-31 win at Wasps earlier in the month, when they finished with 13 men.
On a night when they were without their five England squad members and chose to rest Dan Biggar before next week's Six Nations opener for reigning champions Wales, Saints also suffered the early loss of England back Piers Francis, stretchered off with a potentially serious injury, although initial reports as to his health sound optimistic.
On top of the three Irish tries, former Saints favourite Stephen Myler, third in the list of all-time Premiership points scorers, marked his first return to Franklin's Gardens since leaving to join in 2018 with two successful kicks for the Exiles.
But Irish also fell foul of referee Tom Foley as both scrum-half Ben Meehan and his replacement Nick Phipps were yellow-carded.
Meehan was sin-binned for a tip-tackle on opposite number Reinach, which allowed Saints to use their extra man and go in front for the first time.
A long looping pass had allowed left winger Hassell-Collins to step back inside at the corner to score the opener, Myler's conversion hitting the post before James Grayson's penalty reduced the arrears.
But, with Irish down to 14 men, although Myler kicked a penalty, Reinach then got over on the right and Grayson converted before adding another penalty for a five-point interval lead.
Then came the climax of a very busy night for referee Foley and his TMO when Ratuniyarawa was eventually dismissed for a raised arm at the ruck connecting with Irish prop Harry Elrington. And, although Grayson kicked a third penalty for 16-8, Irish were not finished.
Hassell-Collins had a late try controversially disallowed for being stripped in the tackle by the rapidly covering Reinach, whose initial challenge had been suspiciously high and could have been adjudged a second red card and a penalty try.
But the Exiles did not panic - and in match-winner Polecki, they had the man for the moment as he twice kept a cool head both as try creator and then scorer.
Saints director of rugby Chris Boyd told BBC Radio Northampton:
"My barometer swung past frustration and into anger. But we were the masters of our own demise. A combination of lack of discipline, lack of skill and some poor decision making.
"Consistency is obviously an issue and losing six players takes depth from our selection. But Irish came with a plan, defended well and really we were two minutes away from stealing it.
"We've gone 19 weeks without a break and were desperately keen to finish January on a good note. However, it wasn't to be and we need to regroup and flush out that performance.
"The best thing I can say is no comment as I have a strong opinion on the red and yellow cards that were issued. I'm going to take some splinters and sit on the fence."
London Irish director of rugby Declan Kidney:
"I'll always take a win especially when we achieve it with the last play of the game.
"We didn't deserve to be down at half-time but we knew at the interval that, if we played the same way, we would be capable of winning.
"Even though there was the red card, we couldn't get any possession or territory for quite a period of time but we rode the storm, especially when they missed a couple of kickable penalties.
"However, we didn't give up and started playing again and our aim this season is just to do the best we can, every time we take the field."
Northampton: Tuala; Sleightholme, Hutchinson, Francis, Naiyaravoro; Grayson, Reinach; B Franks, Haywood, O Franks, Coles, Ratuniyarawa, Wood, Harrison (capt), Eadie.
Replacements: Fish, Waller, Painter, Bean, Tonks, Taylor, Symons, Collins.
Sent off: Ratuniyarawa (50).
London Irish: Stokes; Naholo, Rona, Hepetema, Hassell-Collins; Myler, Meehan; Elrington, Porecki, Kepu, Van der Merwe (capt), Coleman, Rogerson, Cowan, Tuisue.
Replacements: Atkins, Dell, Hoskins, Mafi, Donnell, Phipps, Stephenson, Williams.
Sin-bin: Meehan (26), Phipps (63).
Referee: Tom Foley (RFU).
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