Twelvetrees made an impressive try-scoring debut at inside centre in last week's 38-18 victory over Scotland and with Brad Barritt at 13 key to organising England's defence against the threat of Brian O'Driscoll, coach Stuart Lancaster opted to use Tuilagi from the bench when he named his team on Friday.
James Haskell was named at blindside flanker as Ben Morgan is out with a twisted ankle, while Tom Wood switched to number eight and Thomas Waldrom was called in to the replacements in the only other changes announced by Lancaster.
Tuilagi, man of the match in England's stunning victory over world champions New Zealand two months ago, could wreak havoc from the bench on a tiring defence.
"A lot of the players performed very well and with Manu coming back into the equation it gave us some selection decisions," Lancaster said.
"But with the centres playing well last week and Manu still returning to match fitness, having not played for the last four weeks, he and others will give us great options from the bench."
Should England eventually settle on the Twelvetrees-Tuilagi partnership with Owen Farrell at flyhalf, their World Cup-winning coach Clive Woodward will be a happy man after giving the trio a remarkable endorsement.
"One of the finest overseas midfield threes I've ever seen was the New Zealand trio in 2005 - Dan Carter, Aaron Mauger and Tana Umaga," Woodward wrote in Friday's Daily Mail.
"With a midfield of Owen Farrell, Billy Twelvetrees and a fit Manu Tuilagi, England are not a million miles from that."
It is an ambitious description of a combination that has never played before, on the back on a solitary international appearance for Twelvetrees, but Woodward says England must be brave if they are to build a team capable of winning the World Cup on home soil in 2015.
"Stuart Lancaster's priority is to select a team to beat Ireland but his long-term quest to become the number one-ranked side and, ultimately, to win the World Cup requires a genuine second flyhalf at inside centre - someone who can play at 10 if necessary.
"You need a threat outside him who brings speed and physicality to the attack...Manu Tuilagi is still far from the finished article, but what an exciting prospect."
Sunday's bench is a real indication of how far England have come under Lancaster, who began his regime with a collection of largely fresh-faced hopefuls a year ago but can now throw on some match-proven quality.
Hooker Dylan Hartley, who captained England in their third test draw in South Africa in June, has been unable to wrestle the starting shirt back from the impressive Tom Youngs, while 54-cap Toby Flood, now seemingly set to play permanent second fiddle behind Farrell, nevertheless offers a steadying fly-half hand.
Courtney Lawes, one of the most destructive locks in the game who was last year being talked about as a likely British and Irish Lions starter, is another having to bide his time after the eye-catching displays of Joe Launchbury, who made his debut last November.
Scrum-half Danny Care, constantly battling with Ben Youngs for the nine shirt, came off the bench to score England's final try last week, while mighty prop Mako Vunipola is expected to become a starting regular sooner rather than later.
England have not won a Six Nations game away to Ireland for 10 years, their last victory coming under Woodward to complete their 2003 grand slam.
They did win in Dublin in a World Cup warm-up in 2011 though and also swept to an emphatic 30-9 victory in their last Six Nations meeting at Twickenham last March.
Haskell's last Six Nations start was also in Dublin, when England won the title but saw their 2011 Grand Slam ambitions destroyed with a 24-8 defeat to Ireland.
The 27-year-old opted out of last year's championship in order to play club rugby in Japan and then in New Zealand but he has worked his way back into coach Stuart Lancaster's plans.
Morgan had been one of England's most influential players against Scotland but he limped off after 45 minutes with a sprained ankle and Haskell picked up the baton, winning four turnovers in the space of 35 minutes.
Ireland, seeking a fifth consecutive home championship win over England, named an unchanged XV.
England: 15-Alex Goode, 14-Chris Ashton, 13-Brad Barritt, 12-Billy Twelvetrees, 11-Mike Brown, 10-Owen Farrell, 9-Ben Youngs; 8-Tom Wood, 7-Chris Robshaw (captain), 6-James Haskell, 5-Geoff Parling, 4-Joe Launchbury, 3-Dan Cole, 2-Tom Youngs, 1-Joe Marler.
Replacements: 16-Dylan Hartley, 17-Dave Wilson, 18-Mako Vunipola, 19-Courtney Lawes, 20-Thomas Waldron, 21-Danny Care, 22-Toby Flood, 23-Manu Tuilagi.
Ireland: 15-Rob Kearney, 14-Craig Gilroy, 13-Brian O'Driscoll, 12-Gordon D'Arcy, 11-Simon Zebo, 10-Jonathan Sexton, 9-Conor Murray; 8-Jamie Heaslip (captain), 7-Sean O'Brien, 6-Peter O'Mahony, 5-Donnacha Ryan, 4-Mike McCarthy, 3-Mike Ross, 2-Rory Best, 1-Cian Healy.
Replacements: 16-Sean Cronin, 17-David Kilcoyne, 18-Declan Fitzpatrick, 19-Donncha O'Callaghan, 20-Chris Henry, 21-Eoin Reddan, 22-Ronan O'Gara, 23-Keith Earls.