New Zealand, playing without batting rock Ross Taylor who failed a fitness test before the toss, struggled to be six for 93 before Santner and Nicholls put on 84 for the seventh wicket to give the innings some substance.
Santner, who rescued New Zealand in the first match, hit a personal best 67 while Nicholls was out for 55.
With the series locked at 2-2, there was pre-match anticipation the winner-takes-all fifth and final match at Hagley Oval would produce another nail-biting finish.
Colin Munro went on the second ball he faced, caught behind off Chris Woakes for the third time in five innings.
It was a second consecutive duck in a miserable series for Munro who made 49 in the third ODI but totalled only seven in the other four innings.
Mark Wood bowled Kane Williamson for 14 before spinners Adil Rashid and Moeen Ali stepped up to decimate the middle of the New Zealand innings.
Rashid, who finished with three for 42, accounted for Tom Latham (10), Martin Guptill (47) and Colin de Grandhomme (six).
Nicholls, who had totalled only 14 in his previous four innings, knuckled down to play a disciplined innings that included only one four and one six.
Santner had two sixes and four fours in his 67 off 71 balls before he was caught in the deep by Alex Hales off Woakes in the penultimate over.
Woakes, the most economical of the England bowlers finished with three for 32 off his 10 overs.
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