Matthew Breetzke once again stole the headlines, becoming the first batter in ODI history to pass fifty in each of his first five innings, as the Proteas posted 330 for eight.
Breetzke struck 85 from 77 balls, laced with seven fours and three sixes, and shared a crucial stand of 147 with Tristan Stubbs, who made a composed 58 before being run out.
Dewald Brevis recovered from being involved in that dismissal to smash a blistering 42 from 20 balls, punishing England's part-time spin.
Ryan Rickelton (35) and Aiden Markram (49) added useful contributions, while Corbin Bosch's unbeaten 32 from 29 balls ensured South Africa pushed well beyond the par score at Lord's.
Jofra Archer was England's most effective bowler with four for 62, while Adil Rashid delivered a typically classy spell of two for 33 from his 10 overs.
Chasing a record total, England lost Jamie Smith to the first ball and Ben Duckett soon after.
However, Joe Root (61), Jos Buttler (61) and Jacob Bethell (58) rebuilt the innings, keeping the hosts in contention.
Will Jacks injected late momentum with 39, including a reverse-swept six off Senuran Muthusamy, while Archer threatened to snatch victory with a lively unbeaten 27 from 14 balls.
England needed 16 from the final over, but Muthusamy held his nerve to close out the match and restrict the hosts to 325 for nine. Keshav Maharaj claimed two for 59, while Burger, Ngidi and Bosch chipped in with vital wickets.
The victory followed South Africa's dominant seven-wicket win in the opening match at Headingley, sealing the three-match series.
England now face the task of salvaging pride when the sides meet in the final ODI at the Rose Bowl in Southampton on Sunday.
Former international referee Jaco Peyper says new laws being trialled in Super Rugby Pacific will not reduce stoppages and could even have a negative impact on downtime during a match.
Proteas batter Tristan Stubbs has signed a deal to play for English county side Hampshire in their T20 Blast and for Southern Brave in the Hundred tournament.
Tom Banton's composed unbeaten half-century and a ferocious Harry Brook cameo steered England to a six-wicket victory over Sri Lanka in a rain-reduced second T20 international, sealing the series 2-0 in Pallekele.
Quinton de Kock praised Ryan Rickleton's ability to adjust to the No 3 role and believes the rest of the lineup will need to show similar levels of adaptability if the Proteas are to win the T20 World Cup in India.
