Centres Andy Symons and Fraser Strachan, flanker Devante Onojaife and lock Ben Glynn will play no further part for the black, green and gold.
Symons does at least go out on a high as he was man of the match when Saints won their most recent game, the 16-10 Gallagher Premiership success at Worcester Warriors on March 6.
There had been high hopes for Strachan and Onojaife as they progressed through the club's Academy system, but neither player has been able to become a first-team regular.
Glynn joined on a short-term loan deal from Ospreys back in February but was only able to make three appearances, all from the bench.
And the quartet will now depart when their contracts end on June 30.
Strachan's next club has already been confirmed as he will be moving to Ealing Trailfinders in the Championship.
The 21-year-old former Scotland and England age-group international made four first-team appearances in total for Saints and twice won the Premiership Rugby Shield with the Wanderers.
“It’s been an honour in my three seasons at Saints for me to pull on the famous black, green and gold jersey," Strachan said.
“But the time is right for a fresh start for me now, and I’m excited about what’s in store for the next stage of my career.”
Symons arrived at Franklin’s Gardens in the summer of 2018 from Gloucester after stints with Leicester Tigers and Worcester Warriors.
And he will be moving on to pursue an opportunity to play in France.
A serious knee injury halted his debut season in black, green and gold after just three appearances, but on returning this campaign, Symons has notched up a further 14 appearances for Saints, scoring three tries, including a double against Saracens in October.
Symons said: “I have really enjoyed my two years with Northampton Saints and I just want to thank everyone at the club for welcoming me as they have done.
“The time has come for me to move on, but I’ve really enjoyed working with this extremely talented group of players and coaches, and I want to thank the club’s medical staff too for working so hard to get me through a really challenging injury last year.”
Flanker Onojaife departs Saints with six senior appearances to his name, two of which came in the Gallagher Premiership.
The 22-year-old forward also earned international honours during his time in Northampton, representing Scotland Under-20s in the Six Nations, and helped the Wanderers to claim back-to-back Premiership Rugby Shield titles.
“I’ve made some great memories with a fantastic group of players here at Franklin’s Gardens, so of course I’ll look back on my time here with huge fondness,” Onojaife said.
“I really think this rugby community in Northampton is special and I wish the rest of the squad and the coaches the very best for the future.”