Victor Perez claimed the Abu Dhabi HSBC Championship at Yas Links.
Tied for the lead with Francesco Molinari and Min Woo Lee overnight, Lowry never looked comfortable and with his title chances gone by the 14th, he frittered away late shots and closed with a four-over 76 to finish nine behind the winner.
It was the second successive Abu Dhabi Sunday disappointment for Lowry, who was just a shot off the lead heading out on Sunday 12 months ago but triple bogey the first and finished 12th.
This time it fell to 51-year-old Harrington, who was just two off the lead heading into the final round, to provide a thrilling Irish challenge.
But while he charged to within two shots of Perez with five birdies in seven holes in the middle of his round, the birdies dried up and his closing 67 left him just two shots behind the winner in solo fourth on 16-under.
Perez (30), who was just a shot off the lead overnight, birdied six of his first 11 holes to get to 18-under and went on to close out victory by holing a bunker shot for a two at the 17th.
While he bogeyed the last after finding trouble off the tee, his six-under 66 gave him a one-stroke win over Sweden's Sebastian Soderberg (67) and Australia's Min Woo Lee (68) on 18-under.
The Frenchman's third DP World Tour win catapults him to the top of the Race to Dubai and to second in the race for a spot in Luke Donald's European Ryder Cup team.
But it was a thrilling final-round effort from Harrington, who will believe more than ever that he still has the game to frighten the young guns as he looks forward to Major appearances this year in the US PGA, the US Open and The Open.
After following a bogey at the first (where he failed to escape from a fairway bunker) with birdies at the second and fifth, he was four behind Perez when he three-putted from eight feet for a bogey six at the seventh.
But the Dubliner was soon right in the thick of the action as he ripped his approach to four feet at the 186-yard eighth to set up the first of five birdies in seven holes.
After knocking in a 12-footer at the 10th, the three-time Major winner made a four-footer at the 12th, a six-footer for a two at the 13th and a 12-footer at the 14th to get to within two shots of the lead.
Lowry followed early birdies at the second and fifth with bogeys at the sixth and ninth. But while he birdied the 12th and 13th to keep his hopes alive, he dropped five shots in his next three holes.
Under pressure to make birdies, a bogey at the 14th took all the wind out of his sails and after another dropped shot at the 15th, he ran up a triple bogey seven at the 16th, sniping an iron straight left off the tee into the water before duffing his third into the water after a drop.
When Perez three-putted the 14th for bogey, he was tied for the lead with Min Woo Lee and just one ahead of Harrington, who was tied for third with Soderberg.
But the Frenchman birdied the 15th by rifling a 204-yard approach to 13 feet and rolled in the putt to lead by a shot on 18-under from Lee and Soderberg.
Harrington missed from 12 feet at the 15th and never had another birdie chance on the way home, finishing with four straight pars.
Seamus Power tied for 20th on 10-under after a frustrating 69, but he thoroughly enjoyed his fortnight in the Middle East, where he also played in the inaugural Hero Cup.
"Kind of the same as the last couple of days— frustrated," said Power, who never got it going on the greens after opening with a 66 and takes next week off before playing three PGA TOUR events in a row, starting with the Pebble Beach Pro-Am.
"I played better than that and that's the annoying thing. Right from the get-go, I hit a little too much club at the first rolled into a bunker, then had 25 feet for eagle on two and three-putted for par. Then another three-putt on six.
"I had a good chances on four and made eagle at seven but had a bad break at eight. I had a good chance on 10 I didn't make, and an eagle putt on 11.
"Made one at 12, but I had six feet on 13. And a really good chance on 15 and a chance of 16. And then got a bit of a bad break at 18.”
Meanwhile, Leona Maguire fell 11 strokes behind Canada's Brooke Henderson heading into today's final round of the Hilton Grand Vacations Tournament of Champions at Lake Nona.
The Co Cavan star shot a one-over 73 to share 16th on three-under as Henderson's 69 gave her a three-shot lead over Japan's Nasa Hataoka (66) and Nelly Korda (68) on 14-under.