Steward and Van Poortvliet among England changes to face South Africa
George Furbank has been omitted from the matchday 23 completely in a move that paves the way for Steward's return at No. 15, while scrum-half Ben Spencer has also been dropped, with Van Poortvliet set to make his first Test appearance for more than a year.
Furbank and Spencer both started against New Zealand and Australia in England's opening two November internationals, which ended in agonising late defeats.
Those reverses have increased the pressure on coach Steve Borthwick, with England now on a run of four straight losses.
Borthwick has made two other, injury-enforced, personnel changes to his starting 15 after wing Immanuel Feyi-Waboso and flanker Tom Curry were ruled out because of concussions suffered during a 42-37 defeat by the Wallabies.
Ollie Sleightholme, who came off the bench to score two tries against Australia, is given his first start on the left wing, with Sam Underhill chosen at openside flanker.
Springboks coach Rassie Erasmus, speaking earlier Thursday, described Steward as "one of the best in the world".
Van Poortvliet was England's preferred scrum-half before last year's World Cup, but sustained an ankle injury in a warm-up match against Wales and has since been overlooked by Borthwick.
Tom Roebuck fills the bench vacancy created by Sleightholme's elevation to the starting XV.
Saturday's match will be England's first game against South Africa since last year's dramatic 16-15 semi-final World Cup semi-final loss to the Springboks in France.
"We're excited to challenge ourselves against the world's top-ranked team and back-to-back World Cup champions," said Borthwick.
"Test matches against South Africa are always thrilling contests and I'm sure Saturday will be no exception."
England (15-1)
Freddie Steward; Tommy Freeman, Ollie Lawrence, Henry Slade, Ollie Sleightholme; Marcus Smith, Jack van Poortvliet; Ben Earl, Sam Underhill, Chandler Cunningham-South; George Martin, Maro Itoje; Will Stuart, Jamie George (capt), Ellis Genge
Replacements: Luke Cowan-Dickie, Fin Baxter, Dan Cole, Nick Isiekwe, Alex Dombrandt, Harry Randall, George Ford, Tom Roebuck
Coach: Steve Borthwick (ENG)