Joe Schmidt has named the team to play England in Twickenham on Saturday.
Ross Byrne is set to win his third cap, having previously featured against Italy and the USA in the 2018 Guinness Series.
It means Johnny Sexton will miss out on the game after the fly-half sat out training at the start of the week in Ireland’s warm-weather camp in Portugal.
The Leinster playmaker has been recovering from a thumb sprain but Ireland had hoped he would be ready to feature against England.
Rory Best returns to captain the side which includes several players making their first start this season.
Best is joined in the front row by Cian Healy, winning his 90th cap, and Tadhg Furlong. The South Africa-born Munster star, Jean Kleyn, who made his debut against Italy at the start of the month, has been handed another chance to prove his World Cup worth as he partners Iain Henderson in the second row.
The back row sees Peter O’Mahony, Josh van der Flier and CJ Stander get their first outing of the season.
Byrne starts at fly-half outside the returning Conor Murray, while Bundee Aki and Garry Ringrose renew their centre partnership.
Rob Kearney starts at fullback with Jordan Larmour and Jacob Stockdale on the wings.
Jack Carty, who took over from the injured Joey Carbery in the game against Italy two weeks ago, is named in the replacements with Luke McGrath and Andrew Conway as the other back subs.
Sean Cronin and Jack McGrath are in line for their first start of the season off the bench which also includes Andrew Porter, Devin Toner and Tadhg Beirne who all featured at the Aviva Stadium earlier this month.
Ireland (v England): R Kearney, J Larmour, G Ringrose (all Leinster), B Aki (Connacht), J Stockdale (Ulster), R Byrne (Leinster), C Murray (Munster), C Healy (Leinster), R Best (Ulster, capt), T Furlong (Leinster), I Henderson (Ulster), J Kleyn, P O’Mahony (both Munster), J Van Der Flier (Leinster), CJ Stander (Munster).
Replacements: S Cronin (Leinster), J McGrath (Ulster), A Porter, D Toner (both Leinster), T Beirne (Munster), L McGrath (Leinster), J Carty (Connacht), A Conway (Munster).