Khan struck a sublime 103 from 84 deliveries that was generously peppered with nine boundaries and two sixes
Captain Temba Bavuma's century set South Africa on the way to a record run chase at Bloemfontein to win the second one-day international against England and clinch the series on Sunday.
Bavuma made 109 opening the batting as the Proteas overhauled England's daunting total of 342-7 with five balls to spare.
South Africa finished on 347-5 to win by five wickets and lead the three-game series 2-0 with one to play.
With South Africa needing two off the last over, David Miller slammed a six over long-off on the first ball of that last over to seal victory and finish 58 not out from 37 balls.
Marco Jansen was with him on 32 not out as South Africa timed their innings perfectly to set a new record for the highest successful run chase in an ODI at Mangaung Oval.
Bavuma set it up with his third ODI hundred. He hit 14 fours and a six to outdo his counterpart, England captain Jos Buttler, who made 94 not out to power England's total.
Buttler top-scored for the English and Harry Brook made 80 in his second ODI appearance after getting out for a duck on debut in the series opener.
Moeen Ali hit a rapid 51 down the order to help take England to their strong total.
But Bloemfontein is known for being batter-friendly and South Africa put four half-century partnerships together and maintained their momentum throughout the chase.
Khan struck a sublime 103 from 84 deliveries that was generously peppered with nine boundaries and two sixes
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