The England winger has been handed the responsibility by head coach Dean Ryan in a side that contains six changes to the one that beat Bucuresti 106-3 in the European Challenge Cup last weekend.
Anthony Allen will make his first Premiership start in place of Mike Tindall who is on England duty, and will partner Simpson-Daniel in the centre.
The only other change in the backs sees Mark Foster return in place of Marcel Garvey on the wing.
But there are three changes in the front row. Patrice Collazo returns at loosehead in place of Nick Wood, James Parkes gets a start at hooker because Mefin Davies is on international duty with Wales and Terry Sigley comes in for Phil Vickery at tighthead.
There is one change in the back row where James Forrester comes in for Luke Narraway after the number eight was released from the England squad.
Peter Buxton will skipper the side for the first time in a competitive match after impressing Ryan during the Issoire Tournament in pre-season.
"I think Peter Buxton has great leadership qualities in the context of the example he sets," Ryan told www.gloucesterrugby.co.uk. "Nobody displays more effort or desire and if people can see him in the situation, they will replicate his actions.
"I am really pleased for him because he takes that extra responsibility really well."
Of Simpson-Daniel's elevation to vice-captain, Ryan added: "James has a great opportunity this weekend and the responsibility he has been given reflects his recognition and standing within the squad at Gloucester."
Ryan is also able to welcome back Forrester, Andy Hazell and Peter Richards from England duty and all will figure - Richards is named on the bench.
"To have these three players back with us is an added bonus," Ryan added. "The back row is an area where we are already strong but both James and Andy are two of our form players at the present time and it is great to have them around.
"I am also pleased for Peter Richards and now we need to get him some serious game-time in the next two or three weeks."
On the bench, Terry Fanolua returns after a knee injury and Adam Balding also makes the matchday 22 for only the second time this season following a facial injury in the first game of the season at Worcester.
There are also recalls for hooker Rob Elloway and prop Gary Powell. Mark Cornwell and Brad Davies complete the replacements. Henry Paul was fit and considered for selection but did not make the final 22.
Newcastle, who have already won away at Northampton and drawn with Leicester, will provide a serious threat tomorrow and Ryan added: "Newcastle will provide us with a huge threat.
"They have individuals within their team who are capable of turning games in the blink of an eye and that is what we have to be wary of."
GLOUCESTER v (Newcastle, Saturday, Kingsholm 3pm): Olly Morgan; Mark Foster, James Simpson-Daniel, Anthony Allen, Rob Thirlby; Ludovic Mercier, Haydn Thomas; Patrice Collazo, James Parkes, Terry Sigley, Quinton Davids, Adam Eustace, Peter Buxton (capt), Andy Hazell, James Forrester. Reps: Rob Elloway, Gary Powell, Mark Cornwell, Adam Balding, Brad Davies, Terry Fanolua, Peter Richards.
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