Derby day fell flat for Saints as an error-strewn first-half performance cost them at rain-soaked Twickenham.
Leicester Tigers took a stranglehold on the game at 20-5 up and they never looked back as they recorded a 23-15 success in front of more than 40,000 fans.
Saints were determined to impress on a day dedicated to raising funds for retired centre Rob Horne, but they could not get the win for him as Tigers stood tall.
Tries from Jamie Gibson, David Ribbans and Mike Haywood were not enough as Saints failed to make an abundance of possession and territory pay.
Tigers proved lethal on the counter-attack during the first half, with full-back Jonah Holmes leading the charge.
And though Saints were only eight points down with 10 minutes to go, they could not salvage anything from a disappointing east midlands derby.
Saints had been dealt a sizeable blow just before kick-off as Courtney Lawes was ruled out with the back spasm that had forced his early exit at Bristol a week earlier. Api Ratuniyarawa came in, with Tom Wood on the bench.
And it was Tigers who had the early bite, applying the pressure and winning a penalty, which fly-half George Ford kicked from in front of the posts.
But Tigers were then dealt their own injury blow when one of their England players, Jonny May, was forced off after just seven minutes.
Saints tried to respond as they booted a kickable penalty to the corner - and their confidence paid off as Gibson got the ball over the line.
Biggar missed the conversion and Ford failed at the other end, spurning a penalty chance after Tigers had put pressure on Dan Biggar and won the decision from referee JP Doyle.
Guy Thompson then led a Leicester break but after kicking ahead, he failed to find the pass to Manu Tuilagi and Saints escaped.
But the home side's scrum was under real pressure early on and after Doyle awarded Tigers another penalty in that area, Ford kicked to restore his side's lead.
And the Leicester advantage was soon even larger as Saints' struggles with the high ball continued.
Biggar lofted the ball up but none of his team-mates could gather, with Adam Thompstone making the take, giving it to Holmes, who offloaded to Ben Youngs for the score.
Ford converted and he was soon doing so again after Saints were cut apart by a Holmes break, which led to a Jordan Olowofela score, despite the best efforts of Harry Mallinder.
At 20-5 down seven minutes before the break, Saints desperately needed to summon some sort of response.
But after their pack hammered on the door, Tigers kept it bolted shut, winning the turnover.
However, from the resulting scrum, the men in white conceded a free-kick, giving Saints one more chance.
And they took it, as relentless pressure paid dividends via a Ribbans try.
Biggar missed the conversion with the final kick of a lively first 40 minutes, with Saints managing to retain hope for the second period thanks to their late score.
But Tigers were on the front foot at the start of the second half and even when Saints did get the ball, they were finding themselves exposed on the counter-attack.
Biggar was pressured into conceding another penalty and Ford did the rest to take his team 23-10 ahead.
Saints were still dominating possession and territory for long periods, but the Tigers defence looked water tight while the men in black, green and gold huffed and puffed with no reward.
But just a minute after he was introduced, hooker Haywood made the breakthrough, peeling off from a lineout drive to dive over the line.
Biggar again missed the conversion, though, meaning he had failed with all three kicks at goal, leaving Saints eight points down with 10 minutes remaining.
Time was running out as Saints introduced Fraser Dingwall for his debut and Wood for his first appearance of the season.
But there was nothing the duo could do as Tigers put the seal on their success.
Saints: Mallinder; Tuala (Collins 32), Kellaway, Burrell (Dingwall 75), Naiyaravoro; Biggar, Reinach (Mitchell 64); Waller (cc) (van Wyk 67), Hartley (cc) (Haywood 67), Painter (Franks 64); Ribbans, Ratuniyarawa; Gibson (Wood 75), Ludlam (Eadie 70), Harrison.
Leicester Tigers: Holmes; Thompstone, Tuilagi, Eastmond, May (Olowofela 8); Ford, B Youngs (Harrison 68); Bateman (Feao 70), T Youngs (c) (McMillan 67), Cole (Heyes 72); Williams, Wells; Denton (Mapapalangi 39 (Lewis 75)), Thompson, Kalamafoni.
Referee: JP Doyle