Byrne made his only Ireland start in last year's World Cup warm up game in Twickenham when England humbled the visitors in a record 57-15 rout. He has won seven other caps off the bench, including February's closer 24-12 defeat by the English.
The 25-year-old Leinster flyhalf got the nod ahead of Billy Burns, the former England Under-20s flyhalf who made his debut off the bench in place of the injured Sexton last week.
With Robbie Henshaw also out through injury, Bundee Aki returns to the centre to partner Chris Farrell while Keith Earls comes in on the wing in place of Munster team mate Andrew Conway. CJ Stander is also back at blindside flanker.
After impressing with his snappy service in the 32-9 victory over Wales, Jamison Gibson-Park retains his position at scrumhalf to keep Conor Murray, a fixture at number nine for almost a decade, on the bench.
The team will be captained for the first time by 24-year-old Leinster lock James Ryan.
15-Hugo Keenan, 14-Keith Earls, 13-Chris Farrell, 12-Bundee Aki, 11-James Lowe, 10-Ross Byrne, 9-Jamison Gibson-Park, 8-Caelan Doris, 7-Peter O'Mahony, 6-CJ Stander, 5-James Ryan (captain), 4-Quinn Roux, 3-Andrew Porter, 2-Ronan Kelleher, 1-Cian Healy
Replacements: 16-Rob Herring, 17-Ed Byrne, 18-Finlay Bealham, 19-Iain Henderson, 20-Will Connors, 21-Conor Murray, 22-Billy Burns, 23-Jacob Stockdale
(Reporting by Padraic Halpin; Editing by Christian Radnedge)