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Owen Farrell moves from centre to fly-half to replace Charlie Hodgson, who has a finger injury.
Northampton's Lee Dickson steps in for Ben Youngs at scrum-half, while Scarlets' Ben Morgan starts at number eight in place of Phil Dowson.
Lock Tom Palmer has been dropped in favour of Leicester's Geoff Parling.
Should fortune favour the brave, England's interim coach Stuart Lancaster could be in for the most satisfying of Twickenham debuts. But if Six Nations rugby is more about the more prosaic virtues of experience, form and proven ability, Saturday's meeting with Wales might turn out to be less pleasant.
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Tuilagi, who was fined £3,000 and warned by the Rugby Football Union after jumping off a ferry following England's World Cup exit in New Zealand in October, has played precious little rugby since because of a hamstring problem and a broken cheekbone and eye socket.
He will link up with new boy Brad Barritt, who impressed against Scotland and Italy, in the centre positions.
Dickson, Morgan and Parling make their first Test starts at Twickenham on Saturday as England look to secure a third successive victory after wins over Scotland and Italy.
"We are looking forward to seeing how Brad and Manu gel together in the centre," Lancaster said.
"Owen has trained throughout and knows our patterns and plays, so we are fully confident in his ability to run the game from 10.
"It's been a good start with two wins but we've got real competition for places and Lee, Ben and Geoff deserve an opportunity to start this game."
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Farrell was chosen in the starting XV ahead of Toby Flood, who makes his return to the squad after a spell out with a knee injury.
The Leicester fly-half will be joined on the bench by fit-again Northampton lock Courtney Lawes.
Hodgson, who scored the two tries England have managed so far in this year's Six Nations, is unavailable after cutting and spraining his left index finger in training this week.
"Charlie cut his finger in training earlier in the week and needed stitches, but it swelled up and there is a sprain there," added Lancaster.
"We assessed him this morning [Thursday] and he cannot grip fully.
"Phil and Ben [Youngs] will provide a different role from the bench and it's great to have Courtney and Toby, who can also give us options in what I am sure will be a full-on encounter.
"The finger injury to Charlie Hodgson is very unfortunate, but may prove a blessing for England. Owen Farrell was always destined to end up at fly-half and looks ready to do the job. Hodgson's absence allows Stuart Lancaster to include the incisive power of Manu Tuilagi, whose line-breaking ability is priceless. Geoff Parling will bring organisation and height to the line-out. Ben Morgan brings a much-needed ball-carrying punch. Lee Dickson's inclusion is vital for England's zip and momentum at the breakdown. For the moment, Ben Youngs has lost his spark."
"It's our first home game of the Six Nations, which we are really excited about, and we are sure the crowd will get behind us just as the travelling supporters have done in Scotland and Italy.
"Playing at Twickenham makes it extra special for us and I know we will get all the encouragement we need."
Wales have won only once at Twickenham in the past 20 years - a 26-19 victory during the Grand Slam season of 2008 - but have impressed with Six Nations victories over Ireland and Scotland.
England forwards coach Graham Rowntree believes the hosts will need to perform "10% better" than in their first two games if they are to defeat Wales.
"Wales play at an intensity, a speed and physicality we haven't played against yet," Rowntree told BBC Sport.
"We've spoken about being 10% better at every component of our game."
It will not be as mild as recent days but a pleasant afternoon in store weather-wise at Twickenham.  With light winds and some sunshine, a very reasonable 11 or 12 degrees is expected.
Full Twickenham forecast
A victory for Warren Gatland's Wales - World Cup semi-finalists last year - would land them their 20th Triple Crown.
"They are the form team of the championship so far, and they will be coming to Twickenham and fancying their chances," added Rowntree.
"They are a team who are always in it until the last minute of the game, always threatening to break free.
"They pose challenges all over the field from the set-piece to the breakdown and, with the amount of people in space, you have to mark them all the time.
"At our stage of development as a team, it's just the challenge we need."
England team to face Wales: 15 Ben Foden (Northampton Saints), 14 Chris Ashton (Northampton Saints), 13 Manusamoa Tuilagi (Leicester Tigers), 12 Brad Barritt (Saracens), 11 David Strettle (Saracens); 10 Owen Farrell (Saracens), 9 Lee Dickson (Northampton Saints). 1 Alex Corbisiero (London Irish), 2 Dylan Hartley (Northampton Saints), 3 Dan Cole (Leicester Tigers), 4 Mouritz Botha (Saracens), 5 Geoff Parling (Leicester Tigers), 6 Tom Croft (Leicester Tigers), 7 Chris Robshaw (Harlequins, capt), 8 Ben Morgan (Scarlets)
Replacements: 16 Rob Webber (London Wasps), 17 Matt Stevens (Saracens), 18 Courtney Lawes (Northampton Saints), 19 Phil Dowson (Northampton Saints), 20 Ben Youngs (Leicester Tigers), 21 Toby Flood (Leicester Tigers), 22 Mike Brown (Harlequins)
Centre Manu Tuilagi returns to the England side as interim head coach Stuart Lancaster makes four changes for the Six Nations game against Wales.