Mata Fifita comes straight in for David McSharry, Connacht's try scorer against Harlequins, and joins Henshaw in an exciting new centre partnership.
Darragh Leader will make his first competitive start for the province at full-back, filling in for the versatile Henshaw.
The 19-year-old Leader, who has only recently been signed to the Connacht Academy, impressed as he came off the bench last weekend for the Connacht Eagles in Athlone. He represented Ireland at Under-19 level last season.
Up front, loosehead prop Brett Wilkinson replaces Denis Buckley. Wilkinson is joined in the front row by tighthead Nathan White, who continues as team captain, and Jason Harris-Wright who earns his first competitive start of the season.
The 24-year-old Harris-Wright has made a notable impression from the bench in both RaboDirect PRO12 clashes with Ulster and his native Leinster. With Naoupu moving forward, Eoin McKeon will done the number 8 jersey.
On the bench, former Stormers player Danie Poolman is set to make his first appearance for the province. Rodney Ah You and David Gannon also return to the bench as replacement forwards.
Speaking ahead of Saturday's encounter at the Liberty Stadium (kick-off 2.30pm), Eric Elwood said: "Over the years, we've had huge physical encounters with the Ospreys and we'll be expecting the same this weekend.
"It's another big challenge but we take great encouragement from our performances of the last few weeks.
"Last Saturday, we went toe-to-toe with the English champions and competed with them for the 80 minutes. We played some great rugby and we'll be looking to do the same this weekend against the Ospreys.
"We know it's going to be a hugely physical battle but we're very much looking forward to the test. The goal for us is to keep improving and continue on our upward curve."
CONNACHT (v Ospreys): Darragh Leader; Tiernan O'Halloran, Robbie Henshaw, Mata Fifita, Fetu'u Vainikolo; Dan Parks, Kieran Marmion; Brett Wilkinson, Jason Harris-Wright, Nathan White (capt), Michael Swift, George Naoupu, John Muldoon, Willie Faloon, Eoin McKeon.
Replacements: Adrian Flavin, Ronan Loughney, Rodney Ah You, David Gannon, Johnny O'Connor, David Moore, Miah Nikora, Danie Poolman.