There are changes to the back row with Galway man Andrew Browne named at blindside flanker and Jake Heenan moving to the openside berth.
In the backs, Fionn Carr makes way for Danie Poolman who is named in his favoured position on the right wing.
Summer signing Craig Ronaldson will start at out-half in his fourth professional appearance for the province since moving from reigning Ulster Bank League champions Lansdowne.
The 23-year-old was named Division 1A Player of the Year after scoring a remarkable 206 points in 16 games last season.
From the replacements bench, former Ireland Under-20 hooker James Rael could make his first appearance in Connacht colours on Saturday evening.
Speaking about the team selection and this weekend's encounter with the Welsh region, head coach Pat Lam said: "Losing both Willie (Faloon) and Jason to injury was a big loss for us as a team, but it presents an opportunity for other young players to step up.
"We're looking forward to Craig's first start at this level. He deserves his opportunity after his work in pre-season and he has done well coming on from the bench in the last three games.
"The Ospreys present another big challenge for us and another step up. They are four-time league champions and are undefeated so far this season. They will come here full of confidence with their returning Lions players.
"But we've had a good week training and we're looking forward to confronting the challenge ahead."
CONNACHT (v Ospreys): Gavin Duffy; Danie Poolman, Robbie Henshaw, Eoin Griffin, Matt Healy; Craig Ronaldson, Kieran Marmion; Brett Wilkinson, Sean Henry, Nathan White, Michael Swift (capt), Craig Clarke, Andrew Browne, Jake Heenan, John Muldoon.
Replacements: James Rael, Rodney Ah You, Ronan Loughney, Aly Muldowney, George Naoupu, Paul O'Donohoe, Dan Parks, Fionn Carr.