It is the girls in green's first trip to English rugby headquarters since a 2004 clash which ended 51-10 in the hosts' favour. Centre Lynne Cantwell and current captain Fiona Coghlan are the only Irish survivors from that game.
Saturday's encounter with England will be broadcast live on RTÉ Two (kick-off 6.20pm) with worldwide coverage on www.rte.ie/live. There will also be live radio commentary on 2fm's 'Game On' programme.
Just as Brian O'Driscoll is taking his final bow on the international stage, so too is his female counterpart Cantwell who has worn the Irish number 13 jersey with distinction for 13 years - with twelve of those at Six Nations level.
She confirmed in a recent column for the Irish Times that this will be her 'last year playing for Ireland', and the 32-year-old is planning to go out on a high with the Rugby World Cup in France following on from the Six Nations.
Cantwell will be facing a couple of her Premiership-winning Richmond club-mates on Saturday evening, with Emma Croker and Rebecca Essex both starting in the English pack.
Living, working and playing rugby in London - she is director of a busy physiotherapy clinic in Fulham - the Dubliner is mindful of the improvements Ireland will need to make for their tilt at a second successive Triple Crown.
"We definitely learned more from the Wales game than the Scotland game. Not that we necessarily played worse, it was just a tougher game regardless of the weather conditions," she told RTÉ's 'The Rugby Show' podcast.
"Our execution of a lot of our individual things we wanted to tweak and address, and our accuracy. Definitely around the ruck area, there's things we changed and tweaked.
"Just a few technical things that we want to bring to the England game because we're going to be up against bigger backs and bigger girls so we need to be a little bit smarter.
"And then naturally the game-plan that we're bringing to England because of the threats that they have, we've tweaked a few things for that as well."
Commenting on the English side, she added: "I think they will be strong. They've made seven changes from their last game against Scotland, so it will revert back to more of a similar team that started against France which would be technically their strongest squad.
"Last year (when we beat them 25-0 in Ashbourne) they still had the same pack as normal, and they do this year so nothing's going to change from a pack point of view.
"They definitely have a few more threats in the back-line but it's nothing we don't know, we haven't played against for years and I don't think we're not able for."
Ireland started the campaign with a record-breaking 59-0 win over Scotland before edging out the Welsh 14-6 in a hard-fought tussle.
Cantwell said Philip Doyle's squad will head to London with confidence having trained well and looked at some key areas since their last outing.
"Everybody's fit and ready to go. We had a one-day session last Saturday, it was a really, really good session and I think it was enough to address a few of the things that we need to change (from the last game).
"It's really important that we put it behind us and look forward to this Saturday, so everybody is really excited this week instead of being nervous...because the build-up to a game is something you should enjoy as well.
"What we've got on our side is that we've got practically the same squad as last year. We think that we're taking it on another notch and we have other challenges that we've set ourselves.
"We're trying to implement a different type of game-plan, so that's been our focus as opposed to the Grand Slam, the bigger picture."
Cantwell and company have had increased media attention and support from the Irish public since last year's Grand Slam success, and the girls will make history in two weeks' time when they run out at the Aviva Stadium for the first time to play Italy.
The Women's game on Saturday, March 8 will kick off approximately 40 minutes after the Ireland men's match against the Azzurri has concluded. Tickets for the Women's fixture are available through Ticketmaster.ie.
"It's all steps in the right direction and I think, in Ireland, we're going to get an awful lot more people watching us hopefully if the weather holds out and they stay on (after the men's game)," said Cantwell.
"In Twickenham the last three years they usually got 5,000, now they've 10,000 and 15,000 watching their matches. They started staying for the first 20 minutes, then the first half and now they're there for the full game, so it's definitely work in progress."
Ireland's most-capped female player with 80 caps, Cantwell was thrilled with the recent visit of Joe Schmidt to the Women's camp.
She spoke about the Ireland men's head coach to Second Captains @ The Irish Times, admitting: "Joe was amazing, he really, really was. We were glued to him literally for every single word - just everything about him was so engaging and enchanting.
"His words, and his actual teaching was fantastic and really, really simple.
"You were just completely engaged, but also his enthusiasm and his willingness to muck in, hit pads or demonstrate and then take the mick out of everybody too! That's all part of parcel of it too, so it was really, really great."