The fly-half superstar, who kicked England to 2003 World Cup glory, will be on the bench and replaced by 20-year-old Danny Cipriani.
Wilkinson, capped 69 times, pays the price following a poor display during England's 15-9 Calcutta Cup defeat to Scotland in Edinburgh three days ago.
Amazingly though, it is the solitary change as England head coach Brian Ashton gives the rest of his players a vote of confidence.
And Wilkinson will now be seen as something of a scapegoat, which is harsh on him in the extreme.
Gifted Cipriani is viewed as Wilkinson's heir-apparent in the England number 10 shirt.
Wilkinson was overlooked for England's 1999 World Cup quarter-final against South Africa in favour of Paul Grayson.
That though, was viewed as a horses for courses selection, whereas on this occasion he has arguably been dropped purely on a loss of form.
Cipriani makes an immediate return to the side after being selected at full-back for the Scotland clash - then axed by Ashton when he was pictured leaving a London night-spot after midnight last Thursday.
Ashton's decision received widespread condemnation, with former England chief Sir Clive Woodward among those who criticised his handling of Cipriani.
But Cipriani is now given a belated first Test start in a side that remarkably shows no other switches following the Scotland shocker.
There are two changes on the bench, where fit-again flanker James Haskell takes over from Luke Narraway and Wilkinson features instead of Charlie Hodgson, but Ashton has stopped there.
Wing Lesley Vainikolo can be among those considered fortunate to escape, yet Ashton has given the players who got England into such a mess an opportunity to get them out of it.
Wilkinson made his England debut against Ireland 10 years ago, and he broke Neil Jenkins' world Test points record of 1090 for Wales and the Lions at Murrayfield when he kicked the first of three successful penalties.
But his general play, notably tactical direction and kicking from hand, fell way below standard, leaving Ashton with little option but to consider fly-half alternatives.
It is unlikely to spell the end of 28-year-old Wilkinson's illustrious England reign, but Cipriani can now make a major statement.
Ashton will look to Cipriani for the creative spark so badly lacking during a Six Nations campaign that has misfired.