The South African had carded the lowest round of his European Tour career with a 63 on day three to put himself in the driving seat and he had extended his lead to four shots by the turn.
Kieffer - fresh off a play-off defeat last week in Austria - came home in 30 to sign for a 62 and pile on the pressure but Higgo kept his cool and registered another 63 to get 25 under and seal a three shot victory.
Higgo's maiden victory at last season's Open de Portugal at Royal Óbidos came in just his seventh event and this triumph at Meloneras Golf arrives in his 24th.
That makes him the fastest South African to two wins in European Tour history not including Major Championships, and the victory could also move him up to a career best 65th on the Official World Golf Ranking.
Including Majors, the only South African to claim two wins in fewer events is the great Gary Player, and Higgo revealed he spoke to Player on Saturday night as he sat on his first 54 hole lead.
"I spoke to Gary last night actually and he just said there is no such thing as a lead and you should play like you're two behind," he said. "That was nice from him. He's said it to me so many times but I've never really had a lead so I've never had to worry about that."
The result also secures a South African double, with Brandon Stone having won the Limpopo Championship on the European Challenge Tour earlier in the day.
"It's unreal," Higgo added. "Jeez, I can't put it into words, it feels amazing. It's quite a relief finishing now.
"It wasn’t over until the last hole really, I knew anything could happen, especially with the wind coming up. It was a bit stressful.
"I am just going to keep going forward. I am playing next week, the week after and see where my game goes. It feels good, I have worked really hard with my coach and everyone back at home, so it feels amazing."
It wasn’t over until the last hole really, I knew anything could happen, especially with the wind coming up. It was a bit stressful
Higgo started the day with a two shot lead and he maintained that with a ten foot birdie putt on the second and doubled it with a spectacular long range chip-in for eagle at the fourth.
Kieffer had birdied the first and eighth from around 12 feet as he also took advantage of the fourth but he gave a shot back on the ninth and was still five back as he turned in 32.
A tee shot to 20 feet on the driveable par four tenth brought an eagle and trimmed the lead but Higgo holed from 30 feet at the ninth to lead by four at the turn.
Another 20 footer from Kieffer at the 11th was followed by an up-and-down at the tenth from Higgo as the duo continued to go head to head.
Kieffer kept his foot down with a pitch to ten feet at the 13th and when he put a stunning approach to three feet at the next, he was as close to Higgo as anyone had been all afternoon.
The leader had a good look at eagle on the par five 13th but had to settle for a two putt birdie, although he could not shake off Kieffer, who chipped in for birdie at the 16th.
Higgo then made a birdie on the par five last with two putts to claim the 500th win by a former Challenge Tour player on the European Tour.
Winther was two under for the day with four birdies and two bogeys after 15 holes but birdied the 16th and 17th before chipping in for an eagle on the last.
Olesen was blemish free with four birdies as he also carded a 66, two shots better than Syme who was in contention before he made a quadruple bogey eight on the 14th, adding to seven birdies and a bogey.
Another Dane in Joachim B. Hansen was at 17 under, a shot clear of English pair Richard Bland and Jack Senior, Dutch duo Joost Luiten and Darius van Driel, Frenchman Matthieu Pavon, German Marcel Schneider and Austrian Matthias Schwab.