Furlong has not played since December after ankle, hamstring and calf injuries, but had hoped to be fit to return against the Welsh. His place in the side is taken by Finlay Bealham, who gets the nod ahead of Tom O’Toole.
"Finlay deserves it," Ireland coach Andy Farrell (47) told reporters on Thursday. "He's playing very well, last time out he scored a hat-trick (of tries for Connacht against Newcastle Falcons in the Challenge Cup)."
Furlong is expected to return for Ireland’s crucial second clash against France in Dublin on February 11.
Sexton has recovered from surgery to his cheekbone and starts alongside scrumhalf Jamison Gibson-Park. Stuart McCloskey and Garry Ringrose continue their partnership in the midfield. Hugo Keenan is at fullback, and Mack Hansen and James Lowe on the wings.
Bealham will pack down in the front row of the scrum with fellow prop Andrew Porter, with hooker Dan Sheehan between them.
Tadhg Beirne and James Ryan are the lock pairing, while Caelan Doris is at number eight, and Josh van der Flier and Peter O’Mahony on either flank.
Farrell confirmed the roof at the Principality Stadium in Cardiff will be closed for the match.
"We wanted it closed to sample the atmosphere and keep progressing on our journey. When the roof is closed there is no atmosphere like it. It's a fantastic stadium," he said.
The coach also dismissed opposite number Warren Gatland's notion that this was a "free shot" for Wales as they were heavy underdogs against the number one ranked Irish.
"There's no free shot in test rugby. Maybe I'll buy him a free shot after the game," Farrell said.
Ireland have won five of their last six tests against Wales, but did lose 21-16 on their last visit to Cardiff in 2021.
Ireland team
Backs: 15. Hugo Keenan, 14. Mack Hansen, 13. Garry Ringrose, 12. Stuart McCloskey, 11. James Lowe, 10. Johnny Sexton, 9. Jamison Gibson.
Forwards: 1. Andrew Porter, 2. Dan Sheehan, 3. Finlay Bealham, 4. Tadhg Beirne, 5. James Ryan, 6. Peter O’Mahony, 7. Josh van der Flier, 8. Caelan Doris.
Replacements: 16. Rob Herring, 17. Cian Healy, 18. Tom O’Toole, 19. Iain Henderson, 20. Jack Conan, 21. Conor Murray, 22. Ross Byrne, 23. Bundee Aki.
