Harrington finished at 16-under-par 271, five clear of the field. The Irishman also won this title in 2002.
Bradley Dredge, who played with Harrington, shared the lead with the Irishman as they went to the 11th hole. However, the Welshman struggled to a double bogey on 11 and never was able to catch up. He drained a birdie putt at the last to finish alongside Anthony Wall and Edward Loar.
That trio shared second place at 11-under-par 276. World No. 6 Ernie Els closed with a 70 to take fifth at minus-10.
For the first three rounds, players competed over three courses -- Kingsbarns, Carnoustie and the Old Course at St. Andrews. Sunday's final round was played at St. Andrews.
Harrington trailed by one entering the round, but he erased that deficit with a 10-foot birdie putt on the first.
Dredge had a tough stance in a greenside bunker at the par-5 fifth. He blasted 45 feet past the pin, but drained that long putt for birdie to regain the lead.
Harrington dropped in a 12-footer for birdie on the ninth to join Dredge at 14 under. At the 11th, Harrington again had a 12-footer for birdie, but Dredge played first.
Dredge's tee shot stopped against the left side of a bunker short of the green and he was forced to play out backwards. He pitched his third onto the putting surface, but two-putted for a double bogey which dropped him to 12 under.
Harrington then made his birdie putt to move three clear of Dredge and two ahead of Loar. No one was able to pressure the Irishman the rest of the way as he played safe down the stretch.
'Obviously my birdie to Bradley's double there on 11 made a big difference to Bradley,' Harrington said. 'But I needed to keep ahead of the others. I was very wary of that.'
At the 14th, Harrington had to blast out of a fairway bunker with his second at the par-5. He reached the back fringe with his third and two-putted for par.
From there, Harrington two-putted for par on each of the next three holes. At the 18th, he pitched his second to 3 feet and kicked in the birdie putt for the convincing win.
'It did give me a bit of comfort the last couple of holes when I had a three-shot lead,' Harrington admitted. 'I knew I could go left all the way home and be safe. After that good par on 14, I knew I had it.'
Harrington, who also won the pro-am portion of this event with his partner J.P. McManus, jumps into second place on the Order of Merit with the victory, his 10th on the European Tour. He is a just over 200,000 euros behind leader Paul Casey.
With a chance to win the Order of Merit for the first time, he said 'it looks like I'll be there' at the Mallorca Classic in two weeks.
After his double bogey on 11, Dredge bogeyed 13 and 17 to fall to minus-10, but a birdie at the last put him at 11 under.
Loar flew up the leaderboard with five birdies in a six-hole stretch from the fifth to grab a share of the lead with Dredge and Harrington at 14 under. However, Loar bogeyed the 11th and stumbled to two more bogeys down the stretch to end in a share of second.
'I was surprisingly calm,' Loar said when he tied for the lead. 'I started holing a couple of putts and all of a sudden, boom I was right there. I had a couple iffy little shots coming in though.'
Wall opened with three straight birdies and turned at minus-11 thanks to birdies on seven and nine. Wall birdied 11 and 12 to get within one of the lead, but he bogeyed the next two holes to slide back down the leaderboard. He birdied 16 then bogeyed 17 to end at minus-11.
Peter Hanson was joined by Casey in sixth place at 10-under-par 278. Henrik Stenson, Lee Westwood, Paul Broadhurst, Simon Dyson, Johan Edfors, James Kingston and Soren Kjeldsen shared 10th at minus-9.