The pair shared an unbeaten stand of 99 as Pakistan won by five wickets with more than a day to spare.
Younis (67 not out) and Akmal (57 not out) rescued Pakistan from a precarious 92 for five Monday.
Younis played a solid innings apart from a difficult caught and bowled chance low down to Shaun Pollock when he had five, while Akmal batted aggressively as South Africa's hopes of a fourth successive Test win receded.
Akmal's first three boundaries, all off Pollock, flew off edges through the slip cordons. Two went between second slip and gully. When South African captain Graeme Smith moved the gully fielder to third slip Akmal edged the ball where gully had been.
But Akmal then played some stirring strokes as he hurried to his half-century off 61 balls with five more fours.
What had been a tense contest ended shortly before tea as Younis and Akmal took their team to victory with a flurry of strokes.
The victory was set up on the first day when South Africa were bowled out for 124, their lowest score against Pakistan. Man of the match Inzamam-ul-Haq then made an unbeaten 92 to take Pakistan to a first innings lead of 141.
But South African hopes were raised when Pakistan, needing 191 to win, were three down with only 48 runs scored.
Younis Khan and Mohammad Yousuf put on 39 before Pakistan had another wobble when Yousuf was caught at gully off Shaun Pollock for 18 and captain Inzamam was leg before for one when he missed a pull against Ntini.
Pakistan made a brisk start to the day with Andre Nel conceding 21 runs in three overs. But a switch of ends for Ntini, who took over from Nel, and the introduction of the accurate Shaun Pollock brought a dramatic change.
With his fourth ball from the northern Duck Pond end Ntini dismissed the left-handed Imran Farhat whose flying edge from a slashed shot was well caught above his head by Jacques Kallis at second slip.
Two overs later new batsman Yasir Hameed pushed Ntini into the covers and went for a risky single. Nel ran in from mid-off, picked up and hit the stumps at the bowler's end for Hameed to be run out.
Mohammad Hafeez, who had started the day confidently but was tied down by Pollock, was third out for 32 when he played across the line against Pollock and was given out leg before by umpire Peter Parker, although replays indicated the ball would have just missed leg stump.
It was Pollock's 415th Test wicket, moving him into eighth place alone on the all-time list, one ahead of former Pakistan left-armer Wasim Akram.
Yousuf, playing in his first Test of of the year after setting a Test run scoring record in 2006, survived a good over from Ntini in which he was twice beaten outside the off stump as he and Younis set about building a partnership.
Younis gave a difficult low return chance to Pollock when he had five.
There was nearly a second run-out three overs before the interval when Yousuf took a quick single to cover and Younis Khan narrowly beat Ashwell Prince's underhand flick on to the stumps.