The Australian had previously indicated he would rest players who had been involved in the British and Irish Lions gruelling 1-1 drawn series in New Zealand earlier this year, and the former Wallaby boss backed up those words by leaving Itoje and Farrell out of his matchday 23 for Saturday’s fixture with the Pumas.
Instead Exeter’s Henry Slade starts at inside centre, with George Kruis and Courtney Lawes the second-row duo.
On the wings, Jones has opted for Elliot Daly and Anthony Watson.
Daly was set to miss England’s opening two November Tests against Argentina and Australia with knee ligament damage but has made a quicker than expected recovery while Leicester flyer Jonny May has been ruled out from facing the Pumas with a hamstring strain.
Sam Underhill starts at openside flanker, with Tom Curry among a list of replacements that includes lock Joe Launchbury.
Jamie George started all three Tests for the Lions but once again the hooker is on the England bench behind captain Dylan Hartley.
“This is our best 23 selected in what is our most important game this year,” Jones said.
“We know that Argentina are a strong team — they were World Cup semi-finalists in 2015 — and we will have to be smart and play well to beat them,” he added.
Saturday’s match will be the fourth time England have faced Argentina since November last year, with the Red Rose winning all three of their previous encounters against the Pumas under Jones, including a 2-0 series win for a side weakened by Lions calls in Argentina in June.
“As a squad we have been preparing for this game since our first camp in August and are excited about playing in front of 82,000 fans at Twickenham Stadium on Saturday,” said Jones.
England play Australia at Twickenham the following Saturday before rounding off their end-of-year campaign against cash-strapped Samoa on November 25.
Mike Brown; Anthony Watson, Jonathan Joseph, Henry Slade, Elliot Daly; George Ford, Ben Youngs; Nathan Hughes, Sam Underhill, Chris Robshaw; George Kruis, Courtney Lawes; Dan Cole, Dylan Hartley (capt), Mako Vunipola
Replacements: Jamie George, Ellis Genge, Harry Williams, Joe Launchbury, Tom Curry, Danny Care, Alex Lozowski, Semesa Rokoduguni