The Northern Irish world number five ended his round in style, hitting an exquisite bunker shot to within two feet at the par-five 18th for a tap-in four, his seventh birdie of the day, as he clinched his 12th PGA Tour victory.
Englishman Casey, hunting his second career win on the U.S. circuit, led by three strokes after 54 holes but had to settle for second place after closing with a 73.
McIlroy, who had not tasted victory on the PGA Tour since the Wells Fargo Championship in May last year, pinpointed his remarkable recovery after a horrible start to Friday's opening round as key to his success at the TPC Boston.
"Those last 15 holes on Friday were definitely a turning point, not just in this tournament, but maybe in my season, to play the last 15 holes in four-under," McIlroy told Golf Channel
The 27-year-old ended up shooting a level-par 71 in the opening round after ominously starting out par; bogey; triple-bogey.
"Then I tweaked my putting grip on Saturday morning, holed some putts on Saturday and went with it and got some momentum," said McIlroy.
"It is amazing to think how I started this tournament and what was going through my mind after three holes, and then all of a sudden (I'm) standing here with a trophy. It is pretty cool."
McIlroy, whose victory lifted him to third in the world rankings, was delighted to regain form after missing the cut at the PGA Championship then tying for 31st at The Barclays in his previous two starts.
"I came off the back of a rough couple of weeks," he said. "I was thinking, 'Here we go again,' and that it was going to be a little bit of a grind and a bit of a struggle.
"Things can turn around quickly in this game and they did for me this week."
American Jimmy Walker, who landed his first major title at the PGA Championship in July, carded a 70 to finish third at 12-under in the second of the PGA Tour's four playoff events, with Australian Adam Scott (65) a further stroke back in fourth.
The top 70 players on the FedExCup points list advance to this week's BMW Championship in Carmel, Indiana, where the leading 30 will qualify for the Sep. 22-25 Tour Championship finale in Atlanta.
(Reporting by Mark Lamport-Stokes in Los Angeles; Editing by Frank Pingue)
