Ireland scrum-half Kieran Marmion will start for Connacht against Grenoble, while centre Robbie Henshaw returns to outside centre for their Challenge Cup quarter-final today.
Marmion missed the Pro12 defeat to Ulster last Friday with a quad injury, while Henshaw was at full-back.
The changes are among five personnel and seven positional switches for Pat Lam’s men.
Shane O’Leary, who spent the 2013/14 season playing with the French opponents, will make his third start for Connacht at out-half.
Up front, recent Ireland international debutants Finlay Bealham and Ultan Dillane start for the first time since their Six Nations involvement.
The back row is reshuffled and features three Galway-born players with Sean O’Brien from the academy coming in to start at blindside flanker.
Eoin McKeon once again moves to openside, while John Muldoon captains the side wearing the number 8 shirt.
Jake Heenan rolled his ankle in Tuesday’s training session and has not travelled with the squad.
Lam said: “We have a few changes to the squad from last week but we are confident that we have a strong team to go over and execute our game plan against Grenoble.
“While it was great to welcome Kieran (Marmion) back from injury this week, it was frustrating to lose Jake (Heenan) who we had initially named to start.
“We understand the challenge we face traveling to play a confident Grenoble side in their home ground.
“But this is knock-out rugby and we are determined to bring a semi-final home to the Sportsground for our supporters.”