De Villiers offered a routine opportunity to Younus Khan at slip when he had just one and made Pakistan pay dearly for that miss by guiding his side to a 3-2 series success with six overs to spare.
Pakistan, who won the toss and elected to bat first at Willowmoore Park on a wicket that had variable bounce, had limped to 205 all out.
The home side always looked comfortable in their chase and the win was sealed with an 88-run stand between De Villiers and Farhaan Behardien (35) for the fourth wicket.
"We got some partnerships together with bat and ball. The whole bowling unit got better as the series went on and today was the best performance of all," said De Villiers, who won the Man of the Series award by scoring 367 runs at an average of over 91.
"Pakistan are a world-class team, there is talent all around their side. It made for a very good series and a very tough series for us."
Pakistan found life at the crease difficult, unable to cope with the tight line of the home bowlers.
Kamran Akmal was the pick of the visiting batsman with a fluent 48 before he top-edged a Robin Peterson delivery on the sweep to Ryan McLaren at square leg.
Plenty of others got starts, but many lost their wicket as they tried to push up the scoring rate.
Younus (29) became a first one day international wicket for Behardien as the part-time seamer dropped a delivery short outside off stump. Younus smashed the ball towards mid-wicket but picked out Hashim Amla, who took an excellent reaction catch.
Shoaib Malik (28), Misbah-ul-Haq (24) and Junaid Khan (25) also got into the 20s, but all fell before they could make a telling impact.
"It was a 250 pitch and the way we started it was gettable. But we did not show responsibility as a batting side," said Pakistan captain Misbah.
"It was a crucial miss [the De Villiers drop], but that happens in cricket. The real problem we were short 50 runs."