The hosts won the toss in the second game of the series and posted 262 for seven in their 50 overs on a slow wicket that produced nothing like the run-fest of Bloemfontein three days earlier.
Hales took England close to their target with a patient 99 from 124 balls as they reached 263 for five from 46.2 overs.
The touring side now lead the five-match series 2-0 with the third game in Pretoria on Tuesday.
AB de Villiers returned to form as he top-scored for South Africa’s with 73 from 91 balls, supported by Faf du Plessis (46) and JP Duminy (47).
News that makes sense
Your trusted source for staying up-to-date with the world around you. Get free daily news updates and analysis, straight to your inbox.
Seamer Reece Topley recorded career-best bowling figures for England of 4-50 from nine overs, including the early scalp of Hashim Amla (4).
England lost opener Jason Roy (14) early in their reply, but Hales, usually an explosive opening batsman, played an innings of accumulation rather than brute force, scoring just eight boundaries.
He fell one shy of his ton when he was caught by South Africa wicketkeeper Quinton de Kock off the bowling of Kyle Abbott after the ball brushed his glove.
England still needed 61 to win but were steered home by an excellent 48 not out from 28 deliveries by Jos Buttler.
He was ably supported by Moeen Ali (21 not out) as the pair put on 61 in just five overs against the wilting home attack to turn a tense run chase into a stroll.
Abbott, restored to the South African side after injury, was the pick of the home bowlers with 3-58 from nine overs.
(Reporting by Nick Said, editing by Ed Osmond)
