Henderson forms a back-row partnership with Ulster colleague Chris Henry and Ireland vice-captain Jamie Heaslip.
O'Connell leads the side and packs down in an unchanged front five alongside Devin Toner, Cian Healy, Rory Best and Mike Ross.
Johnny Sexton has recovered from a thumb injury to join Murray in the half-backs in the same backline that started against England and Wales.
There are a couple of changes on the bench with Rhys Ruddock replacing Henderson who starts and Eoin Reddan coming in for Isaac Boss who is rested this week.
Brian O'Driscoll will become the most capped test player in rugby history claiming his 140th test appearance (132 Ireland & 8 Lions).
Ireland Team & Replacements v Italy, Aviva Stadium, Dublin, 6 Nations Championship, Saturday 8th March kick-off 2:30pm
15. Rob Kearney (UCD/Leinster)
14. Andrew Trimble (Ballymena/Ulster)
13. Brian O'Driscoll (UCD/Leinster)
12. Gordon D'Arcy (Lansdowne/Leinster)
11. Dave Kearney (Lansdowne/Leinster)
10. Jonathan Sexton (Racing Metro 92)
9. Conor Murray (Garryowen/Munster)
8. Jamie Heaslip (Dublin University/Leinster)
7. Chris Henry (Malone/Ulster)
6. Iain Henderson (Ballinahinch/Ulster)
5. Paul O'Connell (Young Munster/Munster) CAPT.
4. Devin Toner (Lansdowne/Leinster)
3. Mike Ross (Clontarf/Leinster)
2. Rory Best (Banbridge/Ulster)
1. Cian Healy (Clontarf/Leinster)
16. Sean Cronin (St. Mary's College/Leinster)
17. Jack McGrath (St. Mary's College/Leinster)
18. Martin Moore (Lansdowne/Leinster)
19. Rhys Ruddock (St Mary's College/Leinster)
20. Jordi Murphy (Lansdowne/Leinster)
21. Eoin Reddan (Lansdowne/Leinster)
22. Paddy Jackson (Dungannon/Ulster)
23. Fergus McFadden (Old Belvedere/Leinster)