The 21-year-old came off the bench for a brief cameo in the 22-17 defeat in Durban - but he will now be given the chance to impress as England look to add a cutting edge to their backline.
Toby Flood and David Strettle also come into the back division, with Ben Foden returning to full-back.
Flood replaces the benched Owen Farrell at fly-half, with Joseph coming in for the injured Brad Barritt - although Manu Tuilagi will shuffle across to inside centre.
With Mike Brown injured, Foden will wear the No.15 jersey, allowing Strettle to return on the wing.
Lancaster has made two further changes on the bench, with Alex Corbisiero and Alex Goode coming into the squad.
Lancaster said: "I am delighted for JJ. He has trained very well and showed against the Barbarians and in his short time on the field in the 1st Test that he is ready to make the step to international rugby.
"To have two 21-year-old centres is exciting and we are looking forward to seeing this combination in action.
"Owen has had a fantastic season and I am sure he will make a significant impact from the bench.
"However, Toby has waited patiently for his opportunity and the time is right to allow him the chance to demonstrate his experience and skills in what will be a very tough challenge.
"It's a shame for Mike Brown who worked hard to get that Test start but Ben Foden naturally reverts to full back and we return to the wing partnership of David Strettle and Chris Ashton that serves us well in the Six Nations."
England: 15 Ben Foden (Northampton Saints), 14 Chris Ashton (Northampton Saints), 13 Jonathan Joseph (London Irish), 12 Manusamoa Tuilagi (Leicester Tigers), 11 David Strettle (Saracens), 10 Toby Flood (Leicester Tigers), 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)Replacements: 16 Lee Mears (Bath), 17 Alex Corbisiero (London Irish), 18 Tom Palmer (Stade Francais), 19 Phil Dowson (Northampton Saints), 20 Lee Dickson (Northampton Saints), 21 Owen Farrell (Saracens), 22 Alex Goode (Saracens).
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