There is one other alteration on the replacements bench as Luke Narraway makes way for the fit-again James Haskell, who will provide back row cover.
Wilkinson kicked himself into the record books last Saturday against Scotland, with his three penalty goals making him world rugby's record points scorers on 1099 points - ahead of retired Wales out-half Neil Jenkins (1090).
But the 2003 World Cup winner's place-kicking was not enough to keep him in England's starting line-up. It is the first time Wilkinson has lost his place since Paul Grayson was preferred to him for England's 1999 World Cup quarter-final defeat to South Africa.
The change at out-half completes a remarkable turnaround for Cipriani, who lost his place at full-back for the Scotland game due to disciplinary reasons.This weekend's game will mark his first start for England and third cap in all.
ENGLAND TEAM & REPLACEMENTS (v Ireland, 2008 RBS Six Nations, Twickenham, Saturday, March 15, kick-off 3pm local time):
15 - Iain Balshaw (Gloucester) 34 caps
14 - Paul Sackey (London Wasps) 14
13 - Jamie Noon (Newcastle Falcons) 30
12 - Toby Flood (Newcastle Falcons) 16
11 - Lesley Vainikolo (Gloucester) 4
10 - Danny Cipriani (London Wasps) 2
9 - Richard Wigglesworth (Sale Sharks) 3
1 - Andrew Sheridan (Sale Sharks) 23
2 - Lee Mears (Bath) 22
3 - Phil Vickery (London Wasps) 63 (capt)
4 - Simon Shaw (London Wasps) 47
5 - Steve Borthwick (Bath) 36
6 - Tom Croft (Leicester Tigers) 2
7 - Michael Lipman (Bath) 6
8 - Nick Easter (Harlequins) 15
16 - George Chuter (Leicester Tigers) 20
17 - Matt Stevens (Bath) 25
18 - Ben Kay (Leicester) 57
19 - James Haskell (London Wasps) 5
20 - Paul Hodgson (London Irish) 0
21 - Jonny Wilkinson (Newcastle Falcons) 69
22 - Mathew Tait (Newcastle Falcons) 22