The hard-running Ioane missed the Wallabies' last two matches with a knee injury but is restored to the number 14 jersey, replacing neck-injury victim Pat McCabe.
Berrick Barnes is selected at full-back, forcing Mike Harris to settle for a place on the bench, after his second-half substitute appearance in the 33-6 rout in Paris.
Australia's scrum was pulverised by France last week so the return of tighthead Ben Alexander is timely.
A wrist injury has prevented Alexander from playing since last month's 25-19 win over Argentina at Rosario, which sealed second place in the Rugby Championship.
Completing the changes is Sitaleki Timani's selection in the second row after missing out against France because of a tight lower back.
Alexander and Timani take over from Kane Douglas, ruled out with knee ligament damage, and Sekope Kepu.
Australia were hit by the loss of outstanding openside David Pocock earlier in the week.
Pocock was expected to make his comeback from a knee problem at Twickenham, only for a scan to reveal he has incurred a calf strain.
The promising Michael Hooper continues at seven in his absence, while Kurtley Beale is asked to pull the strings at fly-half once more.
There are only five survivors from the last meeting between England and Australia - Beale, Adam Ashley-Cooper, Nathan Sharpe, Alexander and Benn Robinson appeared in the 35-18 defeat at Twickenham in 2010.
The Wallabies have been decimated by injury and set off for their European without playmakers Will Genia and Quade Cooper, among many others, in a situation described by coach Robbie Deans as "carnage".
England have been installed as odds-on favourites to retain the Cook Cup and Deans has demanded his tourists rise to the occasion.
"There aren't too many challenges in Test rugby that are greater than playing England at Twickenham," Deans said.
"We are playing an England side that has been building up under its new leadership, and will see Saturday as the chance to lay down a marker for the future.
"They will be excited by the opportunities they saw out of our performance last weekend.
"But it goes both ways - Saturday is a significant opportunity for us as a group as well.
"It's going to be a great occasion, and one that the whole group is looking forward to."
Australia: B Barnes (NSW Waratahs); D Ioane (Queensland Reds), A Ashley-Cooper (NSW Waratahs), B Tapuai (Queensland Reds), N Cummins (Western Force); K Beale (Melbourne Rebels), N Phipps (Melbourne Rebels); B Robinson (NSW Waratahs), T Polota Nau (NSW Waratahs), B Alexander (Brumbies), S Timani (NSW Waratahs), N Sharpe (Western Force, captain), D Dennis (NSW Waratahs), M Hooper (NSW Waratahs), W Palu (NSW Waratahs).
Replacements: S Moore (Brumbies), J Slipper (Queensland Reds), S Kepu (NSW Waratahs), R Samo (Queensland Reds), L Gill (Queensland Reds), B Sheehan (Western Force), M Harris (Queensland Reds), D Mitchell (NSW Waratahs).