The Northern Irish world number one, 26, finished on 21 under par with a final round 69 in North Carolina to earn his second win at Quail Hollow.
America's Patrick Rodgers and Webb Simpson tied for second on 14 under.
"Everything is firing on all cylinders for me," said McIlroy. "I'm a more controlled player these days. I've learned how to finish things off."
He added: "I felt if I made six birdies there was no chance of anybody catching me.
"I did what I wanted the last few weeks, got a couple of wins, got myself up the Fedex Cup standings and solidified my positions in the rankings."
It was an 11th PGA Tour victory for McIlroy, who shot his lowest career round of 61 on Saturday to lead by four strokes going into the final day and break his own Quail Hollow course record, set in 2010.
A bogey at the par-three second, where he three-putted, was his first blemish since the first round but he made the turn at 19 under.
He held form to ease past the previous tournament record of 16 under set by Anthony Kim in 2008.
McIlroy, who won the WGC Match Play title two weeks ago, now has six top-10 finishes in his last eight PGA Tour starts.
Rory McIlroy won the Wells Fargo Championship by seven strokes, setting a new tournament record score of 267.