Humphreys is being rested as a precaution after sustaining a slight hamstring injury in training.
McLaughlin has also changed the entire front row with Paddy McAllister, Nigel Brady and Tom Court replacing Bryan Young, Andi Kyriacou and Declan Fitzpatrick.
The final change to the starting line-up sees Paddy Wallace join fellow Ireland international Andrew Trimble in the back-line as he replaces Luke Marshall at inside centre.
The second row and back row combinations remain unchanged from last weekend's bonus point win over Cardiff and Johann Muller will again captain the side.
Robbie Diack and Scotland's Simon Danielli have been named amongst the replacements and will hope to make a big impact off the bench.
Ulster have beaten Aironi on three occasions this season and a fourth victory would continue their charge towards the Magners League play-offs.
Speaking ahead of the game, Brian McLaughlin said: "Last Friday night we showed how we can play and the way we want to play.
"We're very pleased with how the youngsters played for us and that is all credit to our Academy and the work of Jonny Bell, Gary Longwell and Niall Malone. We have increased the depth of our squad greatly.
"(The Aironi fixture) is a potential banana skin for us. It's a game that if we are complacent in, Aironi are a good enough side to smack you in the teeth and that's something we've got to be very careful of.
"They are not an easy side to play against but the emphasis must be on how we perform," he added.
ULSTER (v Aironi Rugby): Adam D'Arcy; Andrew Trimble, Nevin Spence, Paddy Wallace, Craig Gilroy; Ruan Pienaar, Paul Marshall; Paddy McAllister, Nigel Brady, Tom Court, Johann Muller (capt), Tim Barker, Chris Henry, Willie Faloon, Pedrie Wannenburg.
Replacements: Andi Kyriacou, Declan Fitzpatrick, Jerry Cronin, Neil McComb, Robbie Diack, Luke Marshall, Simon Danielli, Tommy Seymour.