George Furbank and Heinrich Brüssow will not play for Saints again this season - but there is much better news on several other key first-team players.
Dylan Hartley, James Fish, David Ribbans, Alex Moon, Fraser Dingwall and Piers Francis are all available for selection ahead of Saturday's crucial Gallagher Premiership game against Exeter Chiefs at Sandy Park.
It means Saints boss Chris Boyd has some huge selection decisions to make for the final-day clash.
Boyd knows that if his side can win at Exeter, they will be guaranteed a play-off place, regardless of what Harlequins do in their game at Wasps.
If Saints lose, it could open the door for Quins should Paul Gustard's men win at the Ricoh Arena.
And when asked about selection, Boyd, who has steered his side to three successive away wins in the Premiership, said: "It is (difficult) and you can't bring all those guys back in one go so you've got to get the balance between the group that has done really well for us during the past month versus the group you think is going to do the best job against Exeter - it might be the same group or it might be different.
"We'll have a few tweaks, I'd imagine."
Full-back Furbank has been one of Saints' star men this season, but the concussion he sustained against Harlequins last month means he will play no further part in the title bid.
Brüssow suffered concussion in the defeat to Gloucester at Franklin's Gardens in April and will also be sidelined until next season.
"Neither of those guys will appear again this season," Boyd said.
"They've got protocols to finish and get through and we'll give them the summer off to get their bits and pieces sorted out.
"Hopefully they'll be back next season ready and raring to go."
Ribbans has been been out since picking up an ankle injury during the defeat at Saracens in March, while Moon has been missing since last month, also with an ankle problem.
But Boyd said: "He (Ribbans) trained yesterday and today and we normally announce our team firmly at the start of the week but we've got a couple of to-be-confirmeds and he's one who we'll wait and see where he's at on Thursday before we make our final decision.
"He got through most of training today pretty well.
"Him and Moony have both grown well this year in that lock department.
"Alex Coles, a young boy who played for us against Worcester last time out and who will be in the England Under-20s squad this summer, answered the call for us and did a really good job so we've got some good young fellas in that space.
"Ribeye (Ribbans) has been good for us this season.
"Moony has been out for three or four weeks but he was close to playing in the Worcester game and he's trained fully this week.
"He hasn't had any issues so he's certainly available."
Talented young centre Dingwall, like Ribbans, suffered an ankle injury at Saracens a couple of months ago.
But Boyd said: "Fraser trained fully today and Monday.
"He wasn't ready for the Worcester game but he's available for selection now, but so are Piers Francis, Luther (Burrell) and Hutch (Rory Hutchinson)."
Saints have endured plenty of injury problems at hooker, but their selection options are looking far healthier ahead of this week's game.
Hartley, who has not played since December 21 after having knee surgery, is back in full training, with Fish returning from concussion.
Reece Marshall and youngster Samson Ma'asi have been the men in possession of the shirts in recent weeks.
"Fish is ready for selection," Boyd said.
"A few weeks ago we had to try to extract Darren Dawidiuk out of Coventry because we were down to one hooker out of five, but the only hooker who is not available for selection now is Mikey Haywood, who had that ACL that he's been rehabbing. He won't be available until part way through next year.
"We've got some choices to make in that hooker space.
"Reece and Fish have done a pretty good job for us in the past three or four months with Dylan and Mikey missing.
"They've done a really good job so we'll make a decision on Thursday based around what's best for the team in terms of who will fill that No.2 spot and who will fill that No.16 spot.
"It has been a long time for Dylan and he's getting itchy but he also knows it's the wrong thing for the team if he's not 100 per cent ready to play, even if it's off the bench.
"You've got to factor in the possibility that someone might go down after five minutes.
"The problem with a lower limb injury is that not only have you got to get over the injury, you've got rehab on that injury and you've also got your cardio stuff to do so we've got to make sure his lungs are ready to go.
"But he's trained well on Monday and today and at this stage he's available for selection."