Saints will be without England stars Courtney Lawes and Dylan Hartley for the first game since Jim Mallinder's departure.
Lawes has to be rested due to the number of minutes he has racked up for club and country this season, while Hartley is ill and will also miss the trip to face Ospreys.
Stephen Myler, who picked up a calf injury during the 43-32 defeat to the Welsh region at Franklin's Gardens last Saturday, is also absent for the Champions Cup clash.
George North will also play no part as he continues to edge closer to fitness following the knee injury he picked up against Saracens in October.
Kieran Brookes (hand), Tom Collins (foot), Alex Waller (arm) and Charlie Clare (knee) are also missing for Alan Dickens' first game in interim charge.
Dickens has made a total of five changes, with Mike Haywood, Michael Paterson, Jamie Gibson, Tom Wood and Tom Stephenson coming into the team.
Ben Foden will skipper the side in Swansea.
Future Saints fly-half Dan Biggar has been named on the Ospreys bench, alongside Wales team-mate Rhys Webb.
Justin Tipuric comes into the side at seven, while Ben John starts at 14 in the absence of Hanno Dirksen, who was sent off late on in the game against Saints last weekend.
Ospreys: Evans; John, Fonotia, Watkin, Hassler; S Davies, Habberfield; Smith, Baldwin, Arhip; B Davies; Wyn Jones (c); Lydiate, Tipuric, Cracknell.
Replacements: Otten, James, Fia, Beard, McCusker, Webb, Biggar, Beck.
Saints: Mallinder; Tuala, Horne, Stephenson, Foden (c); Francis, Groom; Van Wyk, Haywood, Ford-Robinson; Ribbans, Paterson; Gibson, Wood, Harrison.
Replacements: Marshall, Ma'afu, Hill, Ratuniyarawa, Ludlam, Reinach, Burrell, Pisi.