Head coach Stuart Lancaster has also opted to move Ben Foden to the wing to replace the injured David Strettle in Durban, with Harlequins' Mike Brown coming in at full-back.
In all Lancaster has made four changes from the side which beat Ireland in their final Six Nations game in March.
Ben Youngs is preferred at scrum-half to Lee Dickson and will partner Owen Farrell, who moves back to number 10 after starting at inside centre in the recent Barbarians match.
Dickson will have to make do with a place on the replacements' bench along with fit-again Leicester fly-half Toby Flood, who has been out for the past month with groin and ankle injuries.
Scrum-half Danny Care, back in the squad after being overlooked for the Six Nations due to a string of off-field incidents, must bide his time before a recall.
Flanker James Haskell, back in contention for the first time since the World Cup, also sits the game out after only linking up with the squad this week.
Marler, 21, is given his opportunity at loosehead after an outstanding season for the Aviva Premiership champions.
Alex Corbisiero, who held that position throughout the Six Nations, has been held back in training by a knee injury this week after recovering from a biceps operation.
Johnson, 29, gets his chance with Leicester's Tom Croft missing the three-Test tour through injury.
And with Strettle having been troubled by a slight calf strain, Lancaster has decided to explore the option of playing Foden out wide in the clash at Kings Park.
Lancaster said: "Tom and Joe have had great seasons at their clubs and have worked really hard to get this chance, both are in great form and have really impressed in training.
"Equally, Mike Brown has been outstanding for Harlequins.
"By moving Ben to the wing we retain his strike power and aerial skills and can utilise not only Mike's attacking and defensive assets, but we can also call on his left-footed kicking game.
"Selection is competitive in lots of positions, particularly at scrum-half.
"We are really pleased with Ben's form and he knows our systems well.
"Lee, if he gets his chance from the bench, I am sure will make an impact and Danny will get his opportunity to press his case, as will the others, in the first midweek game on Wednesday.
"We have made no secret of how tough this series will be but it is an opportunity we are looking forward to and I am confident that we can perform."
Another uncapped player, London Irish centre Jonathan Joseph, is also among the substitutes.
England team: M Brown (Harlequins); C Ashton (Northampton), M Tuilagi (Leicester), B Barritt (Saracens), B Foden (Northampton); O Farrell (Saracens), B Youngs (Leicester); J Marler (Harlequins), D Hartley (Northampton), D Cole (Leicester), M Botha (Saracens), G Parling (Leicester), T Johnson (Exeter), C Robshaw (Harlequins, capt), B Morgan (Scarlets).
Replacements: L Mears (Bath), P Doran Jones (Northampton), T Palmer (Stade Francais), P Dowson (Northampton), L Dickson (Northampton), T Flood (Leicester), J Joseph (London Irish).
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