Flood has been named at inside centre ahead of Mike Tindall, who has been struggling with a dead leg, with Wilkinson pulling the strings at fly-half.
The inclusion for Flood is one of four changes made by Johnson following the 16-12 win over Scotland, with Tom Palmer, Nick Easter and Mark Cueto also handed starts.
With Delon Armitage suspended, Cueto was the obvious option to come in on the wing, with the Sale man unlucky to miss the Scotland game after his hat-trick against Romania.
Palmer is preferred at lock to Courtney Lawes after impressing off the bench at Eden Park, while Easter takes over from James Haskell at No.8.
Lawes and Haskell join Dylan Hartley, Alex Corbisiero and Simon Shaw among the replacements, with Johnson opting for a 5:2 split. That means Richard Wigglesworth and Matt Banahan will cover the back division.
The Wilkinson-Flood axis is nothing new for England. Having played in the role during their days at Newcastle, the duo finished the 2007 RWC final in the positions, while they then teamed up for the 2008 RBS Six Nations.
Johnson, though, has only partnered Wilkinson and Flood together once before - in 2010 - while he previously tried Olly Barkley and Shane Geraghty in the No.12 jersey before abandoning plans for a second playmaker in favour of a powerful ball-carrier
England: 15 Ben Foden, 14 Chris Ashton, 13 Manu Tuilagi, 12 Toby Flood, 11 Mark Cueto, 10 Jonny Wilkinson, 9 Ben Youngs, 8 Nick Easter, 7 Lewis Moody (captain), 6 Tom Croft, 5 Tom Palmer, 4 Louis Deacon, 3 Dan Cole, 2 Steve Thompson, 1 Matt Stevens.
Replacements: 16 Dylan Hartley, 17 Alex Corbisiero, 18 Courtney Lawes, 19 Simon Shaw, 20 James Haskell, 21 Richard Wigglesworth, 22 Matt Banahan.
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