After falling to a loss in the opening match, the stakes were high when the two teams arrived at Old Trafford.
With new captain Jos Buttler staring down the prospect of a third series defeat, it was make or break time for the hosts, who lost five of seven white-ball games this month.
Defending a total of 201 all out in a rain-reduced 29-over contest, England's Reece Topley, David Willey and Sam Curran performed left-armed magic as they restricted the visitors for a mere 83.
Topley and Willey, who were recalled after a short break, left South Africa in serious bother at six for four, before fellow left-hander Curran joined the wicket party with his fourth delivery to make it 27 for five.
The Proteas needed a miracle, and at one point it appeared they might get one as returning light showers forced the hosts to dash through their overs.
However, as England rushed to complete the game, it only made them more dangerous as the introductions of Adil Rashid and Moeen Ali sharpened their attack.
In fact, the two spinners took the last five wickets and secured the win in the 21st over.
Earlier in the day, England had to lean on their lower middle order to post a serious total after slipping from 52 for one to 72 for five.
Dwaine Pretorius was the chief protagonist as he took three big wickets inside seven deliveries, including Phil Salt, Joe Root and Jonny Bairstow.
Moeen and Buttler both came unstuck, while Liam Livingstone and Curran managed to leave their mark on the board by hitting 73 runs between them.
The series decider will take place at Headingley stadium on Sunday.