The 21-year-old, who will be partnered at half-back by Craig Casey, showed he had the nerve to keep the hosts noses in front of the Pumas after he came on for Jack Crowley on the hour mark last Friday.
On a landmark weekend for the Prendergast family, Sam's older brother Cian, already capped three times, is named on the bench.
Head coach Andy Farrell has made several changes to the starting lineup.
He has rested the likes of Crowley, Jamison Gibson-Park and Hugo Keenan after two tough outings and with a resurgent Australia, coached by former Ireland coach Joe Schmidt, to come on Saturday week.
Farrell has handed debuts to hooker Gus McCarthy and flanker Cormac Izuchukwu.
The latter, whose father is Nigerian and mother Irish, will be kept company in the back row by the experienced 2022 World Rugby player of the year Josh van der Flier and captain Caelan Doris.
"I'm delighted for Cormac and Gus who have impressed with their work-rate and application over recent weeks and months," said Farrell in a statement.
"They have both performed strongly for their Provinces, brought that good form into the recent Emerging Ireland Tour and are now being rewarded for their efforts."
There is a recall for centre Bundee Aki, the 34-year-old the only player dropped from the starting side following the 23-13 defeat by New Zealand a fortnight ago.
Winger Jacob Stockdale, once an automatic first choice under Schmidt, gets his first taste of Test action since a pre-Rugby World Cup match against Samoa last year.
The 28-year-old replaces Lowe.
Jamies Osborne gets a start at full-back, instead of Keenan, after also impressing when he came on in the second-half against Argentina.
Osborne and Prendergast's Leinster teammate Ciaran Frawley returns to the bench having been dropped for the Pumas match following an error-strewn performance against the All Blacks.
However, he can cover both full-back and fly-half positions.
Whilst Osborne and Prendergast steadied the ship after a rocky opening 20 minutes of the second-half against Argentina, Farrell had been pleased by the performance in the first period.
Nevertheless with a victory over Wales already under their belts the crowd-pleasing Fijians will be optimistic they can also beat an Ireland side that has thusfar in November been way below their best.
"There were signs of improvement last weekend," said Farrell.
"This week has been about building and embracing the challenge of a talented Flying Fijian side who will be coming over to Dublin full of confidence after their recent displays."
Team (15-1)
Jamie Osborne; Mack Hansen, Robbie Henshaw, Bundee Aki, Jacob Stockdale; Sam Prendergast, Craig Casey; Caelan Doris (capt), Josh van der Flier, Cormac Izuchukwu; Tadhg Beirne, Joe McCarthy; Finlay Bealham, Gus McCarthy, Andrew Porter
Replacements: Ronan Kelleher, Tom O'Toole, Thomas Clarkson, Iain Henderson, Cian Prendergast, Conor Murray, Ciaran Frawley, Stuart McCloskey
Coach: Andy Farrell (ENG)
