Marler replaces Alex Corbisiero, Johnson comes in for Tom Croft, while there are also changes at scrum half, where Ben Youngs starts in place of Lee Dickson and in the back three, where Ben Foden moves to the left wing for David Strettle and Mike Brown starts at full back.
England Head Coach Stuart 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 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.
"It's also great to see another young player get Test match experience in Jonathan Joseph and he is delighted to get this opportunity in the match 22 - we are confident he is ready for the step up to this level.
"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."
England (v South Africa, Mr Price Kings Park, 1600 BST, live on Sky Sports HD)
15 Mike Brown (Harlequins)
14 Chris Ashton (Northampton Saints)
13 Manusamoa Tuilagi (Leicester Tigers)
12 Brad Barritt (Saracens)
11 Ben Foden (Northampton Saints)
10 Owen Farrell (Saracens)
9 Ben Youngs (Leicester Tigers)
1 Joe Marler (Harlequins)
2 Dylan Hartley (Northampton Saints)
3 Dan Cole (Leicester Tigers)
4 Mouritz Botha (Saracens)
5 Geoff Parling (Leicester Tigers)
6 Tom Johnson (Exeter Chiefs)
7 Chris Robshaw (capt, Harlequins)
8 Ben Morgan (Scarlets)
16 Lee Mears (Bath Rugby)
17 Paul Doran Jones (Northampton Saints)
18 Tom Palmer (Stade Francais)
19 Phil Dowson (Northampton Saints)
20 Lee Dickson (Northampton Saints)
21 Toby Flood (Leicester Tigers)
22 Jonathan Joseph (London Irish)
Content courtesy of RFU