Scotland's Paul Lawrie posted a 3-under 69 to finish five shots back at 6-under-par 282. The 1999 British Open champion was joined by Holland's Rolf Muntz and Stephen Scahill of New Zealand in a tie for third.
Casey was part of a three-way tie for the lead to start the final round at The Belfry. He coasted at even par until a birdie at the fifth moved him to 11-under and back into a tie for the lead with Harrington, who had jumped out of the gate with a birdie at the first.
That opening birdie was it for Harrington and the Irishman could not shake his troubles throughout the remainder of his round. The door was open for Casey and he took full advantage with an 18-foot birdie at the sixth to take the lead at minus-12.
Casey found trouble with a bogey at the eighth but a birdie at the 12th put him four shots clear of the field.
The 25-year-old brushed off a double bogey at the par-3 14th and reached the green in two at the par-5 15th. He birdied the hole and landed his second shot on the putting surface at the par-5 17th.
Casey two-putted for birdie to return to 12-under, this time with a five-shot edge over his closest competitor. Despite a bogey at the last, Casey comfortably walked away with his first victory on home soil.
'It means a great deal to win this,' said Casey. 'I made my European Tour debut here two years ago on an invitation. That really started things off for me.'
Harrington, who was in contention throughout the week, struggled on Sunday. He bogeyed the ninth to make the turn at 9-under and stumbled with three bogeys on the back nine for a round of 75 to finish at 7-under-par 281.
'It was a tough day. Everything was going to plan until I missed a short putt on the ninth,' said Harrington. 'I don't think it affected me but I just couldn't hole anything. Several times I was going to pick the ball out of the hole but it didn't go in.'
Lawrie had an early run with two birdies over his first six holes and bounced his tee shot into the cup at the par-3 seventh for an ace. Lawrie added a birdie at the 12th but found trouble with a double bogey at the 18th.
'I played lovely and the hole-in-one really got me into things,' said Lawrie. 'All in all I've had a good week.'
Richard S. Johnson collected six birdies and an eagle for a course-record 64 on the Brabazon Course. The Swede finished alone in sixth at 4-under-par 284.
The International Open concluded its run on the European Tour without a single player successfully defending their title. Angel Cabrera had the last chance to do so when he stood one back of the leaders on Sunday but a final-round 78 dropped him out of contention.
The Argentinean finished alongside England's Brian Davis and David Park of Wales at 3-under-par 285.
Simon Khan, Matthew Blackey, Nick O'Hern and David Dixon were one shot further back at 2-under-par 286.