Ford will continue in the No.10 jersey he wore throughout the summer tour to Argentina and the United States when Smith, who was first choice during the Six Nations, was involved in the British and Irish Lions tour.
In another significant selection call, Guy Pepper has been chosen ahead of Tom Curry in the back row with the Sale flanker one of six Lions named on the bench for Saturday's clash.
Marcus Smith was part of Andy Farrell's squad who visited Australia during the summer, but has been overlooked completely with Fin Smith providing playmaker cover from the bench.
England will resume the experiment of fielding Tommy Freeman at outside centre with the Lions wing forming an all-Northampton midfield partnership alongside Fraser Dingwall.
Freeman's positional switch means Immanuel Feyi-Waboso and Tom Roebuck are picked on the wings as part of a back three that is completed by Freddie Steward.
Up front, head coach Steve Borthwick has opted for the less experienced Fin Baxter and Joe Hayes as his starting props with Lions duo Ellis Genge and Will Stuart given replacement roles.
Pepper excelled against the Pumas and the United States during the summer, making his debut and winning two further caps, and the 22-year-old has now been handed the blindside duties in his first appearance at Twickenham.
Sam Underhill takes the No.7 jersey with Ben Earl No.8, a selection call that was made easier for Borthwick once Tom Willis decided to join Bordeaux next season.
Henry Pollock is included on a bench that features a six-two split between forwards and backs.
Luke Cowan-Dickie will win his 50th cap off the bench with Jamie George the starting hooker.
"Luke is a fierce competitor who gives absolutely everything every time he pulls on an England shirt," Borthwick said.
"Reaching 50 caps is a reflection of his consistency, resilience and commitment to the team over many years. We couldn't be prouder of his achievement."
ENGLAND TEAM
Freddie Steward (Leicester); Tom Roebuck (Sale), Tommy Freeman (Northampton), Fraser Dingwall (Northampton), Immanuel Feyi-Waboso (Exeter); George Ford (Sale), Alex Mitchell (Northampton); Fin Baxter (Harlequins), Jamie George (Saracens), Joe Heyes (Leicester), Maro Itoje (Saracens, capt), Ollie Chessum (Leicester), Guy Pepper (Bath), Sam Underhill (Bath), Ben Earl (Saracens).
Replacements: Luke Cowan-Dickie (Sale), Ellis Genge (Bristol), Will Stuart (Bath), Alex Coles (Northampton), Tom Curry (Sale), Henry Pollock (Northampton), Ben Spencer (Bath), Fin Smith (Northampton).
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