The Chris Boyd-coached Northampton side overcame a Leicester side loaded with returning World Cup players to secure a bonus point over their derby rivals and to move to the top of the table, four points clear of Exeter and five points ahead of Bristol who have a game in hand.
Northampton achieved their fourth consecutive win over their neighbours in spite of the loss of their own internationals former All Black Owen Franks, England's Courtney Lawes and Wales' Dan Biggar, who all withdrew before the game with injuries.
Boyd acknowledged the efforts of lesser lights in his squad who stepped up for the side.
"We lost 260 international caps to injury," he said.
"I actually think it was a bonus [to make the changes] because it was a real opportunity for us as a Northampton Saints team missing some really key players to see if we were good enough to do the job.
"The question was about whether we could step up and do the job, and the boys did that today.
"We won and got five points, and we played better in more patches than we did badly. To get a win for our supporters at home makes it a pretty good day. I'm happy," he said.
Leicester are second from the bottom of the ladder.
The win was a boost for Boyd's side who face a home European Champions draw with four times champions Leinster next weekend.
Irish international and former Chiefs and Counties Manukau back Bundee Aki marked his return from injury, and his contract extension at Connacht, with a try in their 24-12 win over the Southern Kings.
Meanwhile, new Wales coach and former Auckland and Fiji coach Wayne Pivac marked the start of his tenure with a 43-33 win over the Barbarians in Cardiff.
Pivac said he was pleased to enjoy the benefits of the week of preparation he had with the side.
"The boys have been fantastic. The preparation was very good.
"They put in a lot of effort. There's a lot of learning to be done, a lot of introductions and people meeting for the first time and getting to know each other.
"They had a tremendous week and I'm just pleased for them that we were able to get the win, get that match behind us and focus on the Six Nations," he said.