The double US PGA Tour champion shrugged off a bogey at the par-four first to fire an eight-under-par 64 in the event hosted by golfing great Jack Nicklaus at Muirfield Village Golf Club.
Donald covered the back nine in a sizzling six-under 30 to end a cool, overcast day well ahead of his nearest challengers.
Australian Jason Day got to seven-under after 15 holes before bogeying 17 and 18 for a 67, finishing joint second with South African Thomas Aiken and Americans Jim Furyk and Ted Purdy.
World number one Tiger Woods, bidding for a record fourth title at Muirfield Village, also bogeyed the par-four last for a five-birdie 69 to lie five strokes off the pace.
Donald, seeking his first US Tour victory since the 2006 Honda Classic, expected nothing special from his day until he holed a 15-foot putt from the fringe to birdie the par-three eighth.
“I guess all good rounds start with a bogey,” the smiling 31-year-old said. “It was kind of a normal every-day round until I got to the eighth and made a nice putt from the fringe there. That kind of sparked off a run of six birdies.”
Donald also birdied the ninth to reach the turn in two-under 34 before picking up further shots at the 10th, 11th, 12th, 13th, 15th and 16th.
“I just got on a hot streak,” he said after needing only 20 putts to post his lowest round on the US Tour this season.
“Eight under through nine holes: that doesn’t happen very often but when you get on that roll, it feels pretty good. So I just kept going and made some birdies.”
Donald, who holed out with a wedge from 48 yards to collect his first birdie of the day at the par-four second, sank five putts between 10 and 25 feet.
“All year, I’ve been trying to focus on hitting more greens and hitting more fairways because I have been putting the ball well,” the Illinois-based professional said.
“I did a good job of giving myself some makeable putts today, which helped.”
American Steve Stricker, winner of the Colonial Invitational on Sunday, and three-time Major Champion Ernie Els of South Africa opened with matching 70s.
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