Wilkinson has been injury free since moving to French club Toulon
Fly-half Jonny Wilkinson will win his first England cap for 18 months as one of three World Cup winners recalled to the side to face Australia on Saturday.
Hooker Steve Thompson makes his first Test start since 2006 while flanker Lewis Moody also returns in the pack.
Number eight Jordan Crane and inside centre Shane Geraghty, both 23, get first Test starts, while prop David Wilson, 24, starts only his second.
The uncapped pair of Courtney Lawes and Ayoola Erinle are both on the bench.
England boss Martin Johnson lost 11 of his original 32-man squad to injury in the lead-up to the match, including seven probable starters.
And the team which will run out at Twickenham will contain only four survivors - captain Steve Borthwick, Tom Croft, Ugo Monye and Care - from last season's 28-14 loss to Australia.
Thompson, 31, completes a remarkable international comeback after being forced to retire from the game in April 2007 by a serious neck injury.
The former Northampton hooker sought a second opinion and then paid back a £500,000 insurance cheque before returning to action with Brive later that year.
He was recalled to the international fold for the summer series against Argentina, earning his 48th cap when he came on as a last-minute replacement in the win at Old Trafford.
Johnson unfazed by England injuries
Dylan Hartley's hamstring problems over the last week opened the door and Hartley, who succeeded Thompson in the number two shirt at Northampton, has to settle for a place on the bench.
"Steve probably realised what he was missing and had the desire to come back," Johnson said of his former team-mate.
"He got himself into shape, worked really hard and he has been fantastic for us these last 10 days, as he was in the summer.
"It is good to have that experience among the younger players."
Thompson and Wilkinson will feature in the same England team for the first time since the 2003 World Cup final against the Wallabies.
Wilkinson's career has been ravaged by injuries since he kicked England to victory in 2003 and the serious knee injury he suffered playing for Newcastle last September means he has not played a Test since the last game of the 2008 Six Nations against Ireland.
However, since regaining full fitness and moving to French side Toulon in the summer, he has been injury free.
Johnson praised the leadership Wilkinson, who will win his 71st cap on Saturday, has brought to the camp.
"He has just been Jonny Wilkinson. He gets on with what he does and does it very well," said the England boss.
"His leadership of the group has been fantastic, particularly his communication with the younger players.
"These guys have seen what he has done for England over the past 10 years. It's a tremendous amount."
Monye, normally a winger but who has been playing at full-back for Harlequins this season, will fill the number 15 shirt with Bath's Matt Banahan and Sale's Mark Cueto on the wings.
Thompson glad to be back
"Ugo's a very composed, mature guy and I think he will handle that position very well," Johnson added. "He has showed real leadership this week with the back three."
Geraghty and Dan Hipkiss form the centre partnership while Danny Care edges out Paul Hodgson for the scrum-half shirt.
Crane, who has previously won two caps off the bench, makes his first Test start in an all-Leicester back row alongside Croft and Moody.
In the front row Thompson packs down between Wilson, who wins his third cap, and Wasps loose-head Tim Payne, while Borthwick and Louis Deacon continue the second row partnership which started both summer Tests against Argentina.
Northampton lock Lawes, 20, is likely to make his Test debut at some stage from the bench.
"He can have an impact carrying the ball, he can have an impact defensively, his set-piece work is good," Johnson noted.
"He's 20 years old and he has got a huge amount of potential to get even better. He has adapted very well, picked it all up very quickly and he has a big future in the game."
England team to face Australia: U Monye (Harlequins); M Cueto (Sale Sharks), D Hipkiss (Leicester), S Geraghty (Northampton), M Banahan (Bath); J Wilkinson (Toulon), D Care (Harlequins); T Payne (Wasps), S Thompson (Brive), D Wilson (Bath), L Deacon (Leicester), S Borthwick (Saracens, capt), T Croft (Leicester), L Moody (Leicester), J Crane (Leicester).
Replacements: D Hartley (Northampton), D Bell (Bath), C Lawes (Northampton), J Haskell (Stade Francais), P Hodgson (London Irish), A Goode (Brive), A Erinle (Biarritz).
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