The Northern Irishman saw off competition from Tiger Woods, Bryson DeChambeau, Justin Rose and Henrik Stenson
McIlroy shot 64, eight under par, finishing 72 holes on 18-under and beating DeChambeau by three strokes.
After the match McIlroy said he didn't expect the level of play to be so high.
"It's so nice to see everything come together finally," he said. "I wasn't that far away. It takes something to click into place. Something clicked into place with my putting obviously."
The win is the 28-year-old’s 14th US PGA Tour triumph, his first since the 2016 Tour Championship.
It suggests that he is in the running to complete a career major Grand Slam by winning the Masters in three weeks.
McIlroy had not won since the day Palmer died in 2016 but ended his drought on the course where Palmer used to greet winners as they left the 18th green.
Tiger Woods, making his second comeback bid after four back operations, was chasing his first victory since 2013.
The 14-time major champion, mired in the longest win drought of his career, has shown form in back-to-back weeks to excite fans for his chances at the Masters, which begins 5 April.