Farrell comes back in for Toby Flood, who scored all England's points against Italy with the boot, at fly-half after recovering from a thigh injury.
Ben Youngs replaces Danny Care at scrum-half while Tom Croft is back in at blindside flanker for James Haskell and Joe Marler returns at loosehead prop for Mako Vunipola.
Lock Joe Launchbury passed a late fitness test and retains his place after injuring his elbow against Italy.
Croft's replacement appearance in that match came only 11 months after breaking his neck.
"I don't think James Haskell did anything wrong. I think his impact coming off the bench in the second half will serve us better and Tom's extra lineout presence will hopefully give us an advantage in terms of securing our own ball and putting pressure on the Welsh ball," said head coach Stuart Lancaster.
"He's clearly a quality player, he played well for us in the Six Nations last year, he's a British Lion and he's had a great impact since he came back into the team."
Vunipola made his first start at Twickenham at the weekend and despite dropping him to the bench, Lancaster expects he will play a big part in the game.
"It was [a] tight [decision between Vunipola and Marler]. I knew both props, whichever way I'd gone, who make a big contribution in the game," he said.
"Joe will give us the solidity in the scrum at the start of the game, when everyone is at their freshest, and as the game wears on Mako will come on and do his thing."
While Flood might consider himself unlucky to be dropped having landed six out of six penalties in England's scratchy win over the Italians, few would argue that Farrell is not ideally suited for the white-hot atmosphere of a Millennium Stadium title decider.
Cut from the same no-nonsense cloth that made his father Andy such a formidable operator in both codes and now a respected coach in his role as assistant to Lancaster, Farrell junior is mature beyond his years.
From the moment he was selected in Lancaster's first game against Scotland last year, he has looked completely at home at the highest level.
Since nailing down the fly-half slot with his superb display against New Zealand in December's stunning victory, he has looked even more comfortable, stepping higher into the line and delivering his passes with the cold-eye of an assassin while also tackling like a flanker.
Youngs, as befits a livewire scrum-half, is a spikier character. Two years ago he was sin-binned in Dublin for throwing the ball away as England blew their Grand Slam hopes in a heavy defeat.
He is a more mature player now and Lancaster is confident that he will not be put out of his stride by the noise and passion rolling down from the stands.
Many of the England team have never played in the stadium, by far the noisiest of the Six Nations venues and only four of Saturday's XV started the corresponding Cardiff fixture two years ago - Youngs, Chris Ashton, Dan Cole and Tom Wood.
In contrast, the majority of the Wales squad have experience of playing in Grand Slam deciders and many of them in a World Cup semi-final.
"A lot of our players haven't played there before, so going to that type of environment is exactly the test we want," Lancaster said.
"We've still got a pretty inexperienced group but they have confidence and character."
Andy Farrell, who made his professional rugby league debut for Wigan at 17 and captained Great Britain at the age of 21, also dismissed any concerns that England's young squad would not be able to deal with the occasion.
"Experience has to start somewhere and to get that first trophy it comes down to your culture and belief and togetherness to get over the line," he said. "We back ourselves there."
Gethin Jenkins will captain defending champions Wales at the Millennium Stadium.
The 32-year-old Toulon prop has recovered from a calf muscle injury to win his 98th cap. He replaces Paul James in the front-row and takes leadership duties instead of flanker Ryan Jones.
Jones broke a bone in his shoulder during last weekend's victory over Scotland and is replaced in the back row by Justin Tipuiric, with Sam Warburton wearing Wales' number six shirt.
Wales boss Rob Howley has decided for a second successive game not to reinstall Warburton - last season's Grand Slam skipper - as captain, preferring instead to let him concentrate on his own game.
That approach worked a treat at Murrayfield five days ago when Warburton delivered a towering man-of-the-match display.
"Saturday is a big finale for the tournament but we have a very experienced squad, who have been in this position before, that have played in big games and that will be important come kick-off," Howley said.
"The players have worked very hard to put themselves in this position for Saturday, with three hard-fought victories on the road."
Two changes on the bench from Edinburgh see James replacing Ryan Bevington and Scarlets flanker Aaron Shingler featuring instead of a promoted Tipuric.
"When you look at the Welsh side, there aren't many weaknesses: they've a strong scrum, good lineout, they're a good defensive team, a great goal-kicker and big, hard ball carriers, they're playing in front of 80,000 people - there's a lot of things going in their favour," warned Lancaster.
"It's going to take an outstanding effort from us - but we've done it before."
Victory for England would give them their first Grand Slam since their World Cup-winning year but they could still win their second championship in three years if they are beaten by fewer than eight points.
Wales would also take the title with a seven-point win as long as England do not score three more tries than them in Saturday's match.
England team: 15-Alex Goode, 14-Chris Ashton, 13-Manu Tuilagi, 12-Brad Barritt, 11-Mike Brown, 10-Owen Farrell, 9-Ben Youngs; 8-Tom Wood, 7-Chris Robshaw (captain), 6-Tom Croft, 5-Geoff Parling, 4-Joe Launchbury, 3-Dan Cole, 2-Tom Youngs, 1-Joe Marler
Replacements: 16-Dylan Hartley, 17-Dave Wilson, 18-Mako Vunipola, 19-Courtney Lawes, 20-James Haskell, 21-Danny Care, 22-Toby Flood, 23-Billy Twelvetrees
Wales team: 15-Leigh Halfpenny, 14-Alex Cuthbert, 13-Jonathan Davies, 12-Jamie Roberts, 11-George North, 10-Dan Biggar, 9-Mike Phillips, 8-Toby Faletau, 7-Justin Tipuric, 6-Sam Warburton, 5-Ian Evans, 4-Alun Wyn Jones, 3-Adam Jones, 2-Richard Hibbard, 1-Gethin Jenkins (Captain)
Replacements: 16-Ken Owens, 17-Paul James, 18-Scott Andrews, 19-Andrew Coombs, 20-Aaron Shingler, 21-Lloyd Williams, 22-James Hook, 23-Scott Williams.