He closed with a three-under 67 to win his second senior major of the year.
Staked to a two-shot lead, Harrington made an eagle on the first hole on the Old Course at Sunningdale and no one got closer than two shots the rest of the way as he became the fifth player with a Senior British Open and a British Open title.
He won by three shots over Thomas Bjorn (67) and Justin Leonard (68).
Australia's Scott Hend, who moved up the leaderboard with a 64 on Saturday, was fourth after carding a final-round 65 to finish six shots off the lead. Compatriot Cameron Percy also shot a 65 to finish seven shots adrift.
Harrington said: "I'm thrilled to have won but very satisfied that I've won a Senior Open with my two Opens. The fact that only five people have ever done it is quite special. I'm quite proud that I've managed to survive this long in the game."
He joined Darren Clarke, Tom Watson, Gary Player and Bob Charles as players to have won the British Open and the senior version.
McIlroy walked around for a bit on the London-area course, though it wasn't much of a show. Harrington seized control late in the third round and never gave anyone much of a chance.
Bjorn made a late charge to get within two shots, but that ended with a bogey on the 16th.
"The only time I saw a leaderboard was on 18," said Harrington, who said he asked his caddie for an update on the 17th hole. "Was fully focused on what I was doing."
The Irishman was surprised to hear McIlroy, who is building a home in London, was at Sunningdale for the final round.
"I didn't see him out there. Was he out there?" Harrington said. "I had the head down all day. I never saw anybody. I had no idea."
Harrington now has 11 titles on the PGA Tour Champions, and he has won multiple times each of the last four seasons.
He won the US Senior Open last month at The Broadmoor. And he nearly won the Senior PGA Championship at Congressional until a late two-shot swing gave the title to Angel Cabrera.
Greg Chalmers, who started the day five shots off the lead, made a 69 to finish seven off, level with fellow Australian Steve Allan.
Richard Green's final round of 66 left him while nine behind Harrington, while Michael Wright was 11 shots in arrears. Mark Hensby's final round of 72 meant he was 13 shots off the lead
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