Tom Wood will skipper a youthful Saints side in the Premiership Rugby Cup opener against Bristol Bears at Franklin's Gardens on Saturday (kick-off 2pm).
A total of 14 fresh players come into the matchday 23 following the 35-21 Challenge Cup win against the Dragons in Newport last Friday evening.
Wingers Ollie Sleightholme and Matt Worley will be making their bow for the first team, with Ampthill tighthead prop Karl Garside also handed his debut.
Will Davis, Charlie Davies, Fraser Strachan and Coventry prop Jack Higgins could all also debut from the bench, meaning the 2000th player in Saints history is likely to run out on to the Gardens turf during the match.
George Furbank lines up at full-back with Luther Burrell and Fraser Dingwall linking up in the midfield, while James Grayson and Alex Mitchell are given another opportunity to develop their blossoming half-back partnership.
Up front, Francois Van Wyk, who came off the bench last weekend, is promoted into the starting front row, while hooker Reece Marshall starts for the first time since April.
Dom Barrow continues his return to action alongside Alex Moon in Saints’ engine room, while a well-balanced back row sees skipper Wood and Lewis Ludlam pack down either side of No.8 Mitch Eadie.
Lock James Craig is set to make his first appearance of the season from the bench.
“It’s sure to be an interesting competition this year given it’s replaced the Anglo-Welsh, and it will be interesting to see how all the clubs sit within it,” said Saints boss Chris Boyd.
“For us, it’s opened up an opportunity for guys coming back from injury, guys that haven’t been able to get themselves onto the teamsheet regularly, and younger guys that are yet to make their first-team debuts.
“So the combination of those three things makes this a really worthwhile exercise; the younger guys have shown enough in the Wanderers games that the skeleton is there for them to be ready, and we’ve mixed them in with some older guys to play around – it’s really exciting to see how they might go.”
Saints: Furbank; Sleightholme, Dingwall, Burrell, Worley; Grayson, Mitchell; van Wyk, Marshall, Garside; Barrow, Moon; Wood (c), Ludlam, Eadie.
Replacements: Haywood, Davis, Higgins, Craig, Onojaife, Davies, Strachan, Kellaway.
Bristol Bears: Pincus; Powell, Bedlow, Pisi (cc), Perkins; Madigan, Stirzaker; Lay, Lindsay, Thomas, Ehizode, Batley, Lam, Heenan, Crane (cc).
Replacements: Capon, Cosgrove, Armstrong, Hawkins, Dun, Cullen, Eden, Lloyd.