Adam Rossington rifled an impressive 67, but the Steelbacks fell well short against Leicestershire Foxes on Friday night.
The Foxes, who hadn't beaten the Steelbacks since 2011, defended their 193 for five in front of another big crowd at the County Ground as Rossington's heroics proved in vain.
Richard Levi and Ben Duckett went early in the Steelbacks reply and although they battled back well, scoreboard pressure eventually told as they finished their reply on 145 for seven.
David Ripley's men lost five wickets for just eight runs between the 13th over and the 16th, giving the Foxes a comfortable 48-run triumph.
Mark Cosgrove was the star of the show for the away side, smashing an eye-catching 79, and Luke Ronchi racked up 59 in a total that never looked likely to be surpassed.
The defeat leaves the Steelbacks knowing that wins in their final two matches, at Yorkshire Vikings on Thursday and at home to Durham Jets next Friday, will be hugely important.
Northants had headed into the Leicestershire clash looking to do the double and make it three wins in a row in this season's competition.
But after the Foxes lost the toss and were put into bat, Ronchi got into his stride early on, taking 12 runs from the first over, bowled by Richard Gleeson.
Ronchi then flashed the ball through the hands of Levi at slip in the second over as the Foxes added another boundary.
Cameron Delport also started to unleash in the fourth over, hitting a couple of sixes off Rory Kleinveldt as the Foxes continued their fast start.
The away side reached 50 without loss at the end of the fifth over, and the Steelbacks needed some inspiration.
It was to come from Rob Keogh, who took a brilliant catch to give Ben Sanderson the wicket of Delport for 26 with the Steelbacks bowler's first delivery of the match.
Leicestershire finished the powerplay on 58 for one and they cruised to 97 for one at the halfway point, giving the Steelbacks a lot of work to do to peg them back.
Ronchi had done most of the damage, but he went for 59 when he top-edged a Sanderson delivery and Steven Crook took an assured catch.
But Cosgrove, who could have been run out on three by Crook, kept going and he smashed a couple of sixes off a Saif Zaib over to move to a 32-ball half-century.
Azharullah got rid of Colin Ackermann, with the batsman caught behind for three, but the Foxes were still in a fantastic position on 157 for three with more than four overs to go.
There was then a calamitous run out as Tom Wells found himself stranded and Gleeson, who had just missed the stumps with a yorker, did the rest.
Cosgrove was next to be run out, but he had already made a telling contribution for the Foxes, racking up an impressive 79 from 48 balls to help his side finish on 193 for five.
With a big target to chase, the Steelbacks needed a strong start in reply, but Levi went early as he miscued one off spinner Callum Parkinson and was caught for 12.
And Duckett, who had hit a brilliant 92 at Worcestershire last Saturday, followed soon after as he was trapped LBW by Clint McKay for just one.
Rossington did manage to get up and running with a few boundaries before firing the ball back at bowler Mathew Pillans, who dropped a sharp chance.
Rossington continued to rack up the boundaries to take the Steelbacks up to 54 for two at the conclusion of the powerplay, and he was to reach his 50 in 31 balls.
The Steelbacks were 87 for two at the halfway stage, with Rossington and Alex Wakely having formed a key 85-run partnership.
But Wakely went for 20 as he couldn't quite clear the ropes and Wells took the catch off the bowling of Gavin Griffiths.
And Wells was at it again soon after, taking the catch that saw Rossington depart off the bowling of Delport.
Delport then grabbed another wicket in the same over as Rob Keogh was also caught by Wells, for four.
That left the Steelbacks on 109 for five and any hopes of a home victory were quickly being extinguished.
Kleinveldt was next to go, for one, as Pillans picked up the wicket, and Zaib followed soon after for the same score, with Delport claiming another victim.
Delport finished with figures of three for 19 and all that was left for the rest of the Foxes bowlers to see out a convincing success.
They did just that as the game finished in unusually tame fashion as Leicestershire beat the Steelbacks for the first time in six matches.
Steelbacks: Levi, Rossington (wk), Duckett, Wakely (c), Keogh, Crook, Zaib, Kleinveldt, Sanderson, Gleeson, Azharullah.
Leicestershire Foxes: Ronchi (wk), Delport, Cosgrove, Ackermann, Ali, Hill, Wells, Pillans, McKay (c), Griffiths, Parkinson.