Root’s 125 helped England post 318 for eight at Centurion, but openers De Kock (135) and Amla (127) put on 239 as South Africa won with almost four overs to spare.
Root’s one-day international career-best spanned partnerships of 125 with Alex Hales (65) and 82 with Ben Stokes (53).
Yet England’s hopes of clinching an unassailable 3-0 lead, and taking their winning run in this format to six successive matches, were blown away as De Kock blazed his way to a fourth hundred in his last six ODI innings alongside back-to-form Amla.