Set to make their maiden appearances for the Red Roses are inside centre Alex Lozowski, tighthead prop Harry Williams and flankers Mark Wilson and Tom Curry.
A further seven uncapped players are on the bench, including winger and Rugby convert Denny Solomona, who got the all-clear after a foot injury
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Only four of the team beaten 13-9 by Ireland in their last international three months ago survive with British and Irish Lions call-ups a major factor in 30 players being unavailable.
Losing to the Irish ended a record-equalling 18-victory streak for a top-tier rugby nation by England, with all but one of the successes coming under Australian coach Eddie Jones.
Survivors from the defeat in Dublin are full-back Mike Brown, fly-half George Ford, skipper and hooker Dylan Hartley and lock Joe Launchbury.
Hartley failed to make the Lions squad despite being the first choice for England while his understudy, Jamie George, got the nod for the tour of New Zealand.
The hooker is set for his 85th Test appearance, which would make him the equal-third most capped England player.
"I'm really excited about the England team to face Argentina this weekend," said Jones.
"I have selected a group of experienced players across the spine of the team as well as four young players who will be eager to go out and play well on their debuts for England.
"Those players have worked extremely hard to get selected over the last few weeks, but I have been impressed with the way the whole squad has trained and gelled together.
"They all realise the opportunity that they have to be involved in this England side and I'm sure they will show that commitment come Saturday.
"We are here to win this series 2-0, but we know Argentina will be extremely tough opposition.
"After a mixed year of results, there will be pressure on them to play well and win in front of a partisan crowd.
"We know Argentina are a very good side having played them earlier this season and they will be desperate to win against us."
England are seeking a record-extending seventh consecutive victory over Argentina, whose last win in matches between the countries came eight years ago.
The second and final Test of the series is set for Santa Fe on June 17.
Team (15-1)
Mike Brown; Marland Yarde, Henry Slade, Alex Lozowski, Jonny May; George Ford, Danny Care; Nathan Hughes, Tom Curry, Mark Wilson; Charlie Ewels, Joe Launchbury; Harry Williams, Dylan Hartley (capt), Ellis Genge
Replacements: Jack Singleton, Matt Mullan, Will Collier, Nick Isiekwe, Don Armand, Jack Maunder, Piers Francis, Denny Solomona
Coach: Eddie Jones (AUS)
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