South Africa, chasing a modest 183 for victory, collapsed to 14 for three inside five overs under the floodlights in this day/night fixture.
But opener Amla responded with a superb 97 not out and, together with Proteas captain AB de Villiers (75 not out) he shared an unbroken fourth-wicket partnership of 172 that put England's meagre total of 182 in its proper context.
Victory, with more than 15 overs to spare, saw South Africa share the series at 2-2.
Amla, who made a brilliant 150 in South Africa's 80-run win in the second ODI in Southampton, was named man of the series for a total of 335 runs in four innings at an average of more than 111.
That followed on from his corresponding award in the Proteas' 2-0 Test series win over England where he scored a South Africa record 311 not out at The Oval.
Amla's combined tally for both series was a colossal 817 runs at 116.71.
"It's been a good summer for me and I'm glad we got to level the series," said Amla.
Setting the tone
"I think the way we bowled set the tone, then me and AB were able to finish it off."
De Villiers added: "We've been a little bit inconsistent, but there's a lot of positives, especially the way we played today. We showed a lot of guts – 2-2 away from home is a good effort."
One consolation for England was that, despite this defeat, they remained top of the 50-over world rankings having won 12 of their last 14 completed matches.
"It's been a disappointing day – 180 on that wicket was nowhere near enough," said England captain Alastair Cook, who scored 51, his side's highest individual tally on the day.
He added: "It's frustrating, we came into this game trying to wrap up the series but you can't do that if we bat like we did.
"We've had a really good year in one-day cricket and hopefully we can take that forward to India in the new year."
Cook, recently appointed England Test captain following Andrew Strauss's retirement, will now have a rest as he is not in the national Twenty20 squad.
"Now I have some time off and I'll turn my attention to the Tests in India," Cook said ahead of a four-match series starting in November.
Amla could only watch as the Proteas slumped at the start of their reply.
Left-hander Graeme Smith fell when he edged Jade Dernbach and James Tredwell held on at the second attempt.
International novices Faf du Plessis and Dean Elgar then both nicked excellent James Anderson deliveries to wicket-keeper Craig Kieswetter.
But de Villiers then pulled two successive short balls from South Africa-born seamer Dernbach for four.
Amla eased paceman Chris Woakes, in for Steven Finn who had a back problem, off the back foot for a typically stylish four through the covers.
He then completed a 63-ball fifty, with de Villiers taking just 54 balls to get to the landmark.
Amla drove off-spinner Tredwell over extra-cover for six and ended the match with a wristy flicked boundary off Dernbach.
In all he faced 107 balls with a six and nine fours.
Earlier, left-arm spinner Robin Peterson took three for 37 after enterprisingly being given the new ball by de Villiers as England, without the injured Jonathan Trott and the exiled Kevin Pietersen, failed with the bat.
Only Cook, Kieswetter (33) and recalled paceman Chris Woakes, with a career-best 33 not out, got past 30.
Peterson had in-form opener Ian Bell lbw for 10 while Ravi Bopara, promoted up the order in Trott's absence despite a run of low scores, and Eoin Morgan both exited for ducks.
Left-handed opener Cook completed a 69-ball fifty but fell meekly when he chipped a return catch to part-time spinner Du Plessis. – Sapa-AFP