It means the five-times capped Rob Kearney moves from the left wing to full-back to take over from Murphy, Tommy Bowe switches from the right wing to the left and Shane Horgan has been promoted from the replacements bench to don the number 14 jersey and make his first start of the 2008 Six Nations.
Asked about Horgan's move back into the team, O'Sullivan said: "We know Shane's experience is huge. We're not bringing a rookie in out the cold for a one-off game. He's a hugely experienced player and he's certainly been chomping at the bit to get back in the team.
"He's pretty fired up to be back on the pitch tomorrow. He brings a lot of experience, a lot of composure and his strike rate as a winger has been very good.
"The fact that we were aware all week of this potential situation - with the two boys injured - we were training with that arrangement all week. I don't think there's any inconvenience there, so we're happy. Shane's experience tomorrow is a big part coming in."
O'Sullivan revealed that having talked to the Ireland medical team, he expects to have both Murphy and Dempsey back in harness for the final game of the championship against England.
"They were close (to making it), in fairness, they were both very close. The two of them were gutted yesterday morning. We gave them fitness tests before training and by the time the warm-up was over, the medics told me both of them hadn't come through.
"I'm very confident we'll have both of them available for selection for next week against England. I'm disappointed, of course, that they didn't make it but you move on very quickly. Yesterday morning we were waiting and waiting and we got the word they were out, and then you change gears and you move on. You can't dwell on these things."
Given that this is his first start at full-back in the Test arena, Kearney's switch to number 15 will be monitored very closely and although admitting that he could come under some aerial bombardment from the Welsh, O'Sullivan has plenty of faith in the Leinster man.
"He's done very well. He's a very grounded young lad, he knows the challenges in front of him. He's keeping very focused on the job and he's a very talented player," explained the Corkman.
"It's an exciting chance for him tomorrow. Again, he's one of these players who is nearly more comfortable at full-back than the wing. He's a talented lad, no more than Geordan or Girvan or Luke (Fitzgerald) who can play across the back-three - that's a huge benefit to have.
"He's looking forward to the challenge tomorrow, starting at 15 for the first time. I've every confidence in him. He's forced his way into the team and has done very well."
O'Sullivan agreed: "(Certainly) it's another step. We know the dynamics of full-back are different to the wing and there'll be more questions asked of him tomorrow...awareness positionally and I've no doubt that he'll be tested under the bomb tomorrow.
"But I think he's aware of all that and he's answered all the questions that have been asked up to now. I've every confidence he'll do the same tomorrow and I think he's ready for it."
Sub-plots and team changes aside, O'Sullivan knows only one thing will matter come 3.15pm or so tomorrow afternoon - the result and a result that Ireland need to keep their season alive, regardless of how many points they require to win by to keep themselves in with a shot of the title.
"I've always been of the opinion, 24 hours before a Test game, that I'd take a one-nil. Your whole focus is on getting a result.
"Sometimes games go well for you and you can kick on and pick up points but I don't think you can go in with that headset.
"If it's a one-point win, a drop goal off the upright or last kick of the game, you take it. And that's what Test rugby is about and that's what we're about tomorrow - getting a result," he added.