Batsman Faf du Plessis blasted the second fastest century in Twenty20 history but it wasn't enough for South Africa as the West Indies produced a record chase to win the second match by four wickets in Johannesburg.
The tourists were set 232 for victory and passed that mark with four balls remaining as Chris Gayle bludgeoned 90 from 41 balls to set up their series-clinching win.
The visitors now have an unassailable 2-nil lead in the three-match series.
It is the highest successful run chase in Twenty20 international cricket, beating India's 211 against Sri Lanka in 2009, with 467 runs scored in under 40 overs.
Du Plessis smashed 119 from 56 balls with 11 fours and five sixes to record the highest score by a South African in the shortest format of international cricket, taking his side to 231 for seven in their 20 overs.
He missed the record for the fastest hundred in Twenty20 cricket by a single ball as he took 46 to reach his ton, one more than compatriot Richard Levi against New Zealand in 2012.
The visitors were well on course for the win as Gayle punished the helpless home bowling along with Marlon Samuels (60 from 39 balls) as the pair took the score to 171 for one before the former was out in the 14th over.
That sent the jitters through the West Indies dugout as they lost four quick wickets, but Darren Sammy clubbed 20 from seven balls to carry the tourists to victory as they finished on 236 for six from 19.2 overs.
The final match is in Durban on Thursday.