Hughes holed 10 birdies in the first round at TPC River Highlands in Connecticut to open up a three-stroke lead on Thursday.
The Canadian, who has struggled since returning from the coronavirus-enforced break, made six birdies on his first nine holes before picking up shots at the second, sixth, seventh and eighth holes.
Hughes is three shots clear of world No. 1 McIlroy, Xander Schauffele and Viktor Hovland.
McIlroy mixed an eagle and six birdies with just a single bogey to start with a seven-under 63.
While Hughes is well clear, the rest of the leaderboard is congested, with another six players a shot further back in a tie for fifth.
Phil Mickelson, Sergio Garcia, Michael Thompson, Tyler Duncan, Noh Seung-yul and Louis Oosthuizen opened with 64s.
Jordan Spieth made a solid start with a three-under 67, to be alongside Jason Day and Justin Rose among others.
Spieth, winless since 2017, was four under through nine holes before a mixed back nine, which included bogeys at 10 and 18.
Also in a tie for 33rd is Abraham Ancer, who produced the shot of the day with a hole-in-one at the 16th.
Meanwhile, former world No. 1 Dustin Johnson opened with a first-round 69, two shots better off than countryman Justin Thomas.
