Wilkinson will pull the strings at the Aviva Stadium just a fortnight before England's opening World Cup clash against Argentina in a new-look midfield featuring Mike Tindall and Manu Tuilagi.
The England side includes a total of six changes from the 19-9 defeat to Wales in Cardiff and provides the strongest indication yet of Martin Johnson's World Cup thinking.
Wilkinson has spent most of the last 18 months acting as England's fly-half understudy, warming the bench as Flood made the position his own.
But Johnson gave each man a start each in the warm-up Tests against Wales as he mixed and matched selection, with the intention of naming his strongest possible team to play Ireland.
Wilkinson has reclaimed the prized England 10 jersey and he returns to the starting line-up fitter than before and, he believes, better for his time on the bench.
"It is a massive pleasure (starting) and it is ultimately what you are after," said Wilkinson, whose last start in a full-strength England side was the 15-15 draw with Scotland in March 2010.
"The experience of being on the bench and having to react to that has been a massive learning one for me. I have benefited hugely from it.
"At the time I probably would have wanted to be in a different role and I may not have been the happiest with it but what I learned - in terms of coming into late parts of games, needing to try and find solutions or hold onto situations - was invaluable.
"I am really pleased with that and I am trying to apply all that and integrate it into a performance now that will be from the first whistle."
Wilkinson may be heading into his fourth World Cup and come through some potentially career-ending injury setbacks - but he is setting new standards on the training field.
The 32-year-old has set a personal best in England's fitness tests and his endurance leaves the rest of the squad in his wake.
"Jonny's ahead of everybody by about 10 seconds. He just doesn't drop off his fitness," said wing Chris Ashton. "I don't know how he does it."
Johnson does, having played with Wilkinson at both the 1999 World Cup and the triumph in Australia in 2003.
"That is what he is about," said Johnson. "However many Test matches he has played or whatever he has done, he is still out there working harder than anyone to be better - whether it is fitness, kicking, tackling, defending, attacking.
"That is why he is such a great example to everybody.
"He has played very well. He deserves this game to start. We think it is the right call for them (Wilkinson and Flood) to swap round and we don't miss a beat."
Johnson insisted the team to play Ireland is not his first XV, not least because injured duo Lewis Moody and Ben Youngs are yet to be considered.
But it was interesting that Johnson revealed Tuilagi had been under consideration for England's Six Nations game against Ireland, only for a hamstring problem to keep him out.
That shows the Leicester tyro has been on the England radar for the last six months and strengthens the argument he will start against Argentina on September 10.
Tuilagi and Tindall represent the 13th England centre combination in the 35 Tests since Johnson was appointed manager after the 2008 Six Nations.
"I don't see it as something new," said Johnson.
"It is going to be exciting. This is a good chance to get Manu on the field. We think he deserves a chance to start another Test match."
Ashton will make his first start of the warm-up campaign after overcoming a foot injury, joining Ben Foden and Mark Cueto in England's established first choice back three.
Richard Wigglesworth starts again at scrum-half as Youngs continues his recovery from a knee operation.
Steve Thompson continues at hooker alongside Andrew Sheridan, who will make his first appearance of the warm-up campaign after recovering from a shoulder operation, and Dan Cole.
Louis Deacon and Courtney Lawes pair up again in the second row, with James Haskell starting at openside flanker, where he played during England's Six Nations title-winning campaign.
Tom Croft returns at blindside flanker with Tom Wood moving to the bench and Nick Easter continues at number eight.
Johnson added: "Let's not worry about the World Cup. Let's play this game. That is what rugby is about. This is a game that gets the blood flowing. Let's go out there and give it a good crack."
Gilbert has released a new line of rugby cleats. The Gilbert Virtuo 8S is part of the exciting new product. Check it out.
The Barbarians are one of the top invitational rugby sides with a long history and classic rugby jersey.
The Nike Tiempo is a solid rugby cleat and one of few styles still made from full-grain natural leather.
The Lions get ready for their matches with this green training jersey. It's what the players wear. Get in the Gear!
A cool looking all black rugby cleat with the high performance adidas is known for. Get in the Gear!
Wear the crest of the British and Irish Lions on your t-shirt. A great look for the summer.
The Lions are ready to get their Australia tour underway. They arrive in Perth on Monday.
The New Zealand All Blacks training jersey for 2013/14. Get in the Gear!
The USA Rugby Pro Alternate rugby jersey is perfect for any fan of the Eagles. Get yours to wear during the summer Test matches.
The NEW All Blacks 2013/14 jersey has arrived at World Rugby Shop. Dare to wear the colors of the All Blacks.