Johnson carded five-under-par 66 to remain on course for a second win in three years at the World Golf Championships event, and a 20th victory of his PGA Tour career.
He finished on 16-under 197 for the tournament, while Northern Irishman McIlroy, who led after the opening round, mixed seven birdies with four bogeys for a 68 to stand alone in second place.
Spaniard Sergio Garcia, Americans Patrick Reed and Patrick Cantlay and Australian Cameron Smith were a distant seven strokes back in a share of third.
Tiger Woods had problems on the greens, four-putting at the 15th and three-putting the next, to slip 10 strokes off the pace with a 70.
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Not content to sit on the lead after starting the day two shots clear, Johnson hoisted his drive over a clump of trees at the par-four second and was rewarded when his ball landed near the front of the green and trundled to near tap-in range.
He made a complete mess of the par-four 10th, however, with his second shot from the rough striking a tree branch and ricocheting to the edge of a line of bushes, from where he found another tree with his third shot.
"I misjudged the lie a little bit," he said of his second shot.
"It shot straight up in the air, hit the tree in front of me and I ended up making a double but I didn't let it bother me because I knew I'm playing well and there were plenty of holes I could make birdie on coming down the stretch.
"I'm driving it well, really controlling distance with the irons. I feel good everywhere."
McIlroy acknowledged it would probably be tough to catch the in-form Johnson, who two weeks ago won a European Tour event in Saudi Arabia.
"I battled," McIlroy said. "Probably didn't hit it as well as the first couple of days, but I hung in there.
"It was hard to stay patient but I feel like my patience was rewarded. I'm still four behind, it's going to be tough, especially against D.J. who's arguably the best player in the world."
(Reporting by Andrew Both in Cary, North Carolina, editing by Nick Mulvenney)
