Harrington wasn't notified he'd be playing in the exclusive event until Saturday, when British Open Champion Ernie Els withdrew with an ankle injury.
The Irishman stepped into the breach, finishing at 9-under 133 to edge U.S. Open winner Webb Simpson by a single stroke.
He assured the win after birdieing three straight holes from the 11th to get to 10-under par, avenging playoff losses in the 2007 and 2008 events.
Simpson posted a 6-under 65 in the second and final round of the Grand Slam, which is normally reserved for the winners of the season's four major championships.
Defending champion Keegan Bradley -- himself a replacement for PGA Champion Rory McIlroy -- posted a 4-under 67, ending in a third-place tie, with Masters winner Bubba Watson (even-par 71) far back at minus-3.