The 37-year-old, who made his European Tour debut in 1999 but has never won on the circuit, and Irishman Peter Lawrie upstaged a parade of the world's finest golfers with matching six-under-par 66s.
One stroke adrift were world number 10 Justin Rose, big-hitting Spaniard Alvaro Quiros, Briton Jamie Donaldson and Swedish duo Niclas Fasth and Richard S Johnson.
Drysdale packed seven birdies into his round but it was the one at the par-five 18th that left the sun-drenched galleries open-mouthed in surprise at the tour's flagship event.
His 212-yard second shot landed in the water guarding the front of the green but bounced back out off some pebbles and he went on to make his four.
"I don't know how it came back out but I'll take that break," Drysdale said. "I was jumping up and down on the fairway and was happy to see where it finished.
"It was one of those strokes that was totally the opposite of what I was trying to hit."
World number 291 Drysdale and 2008 Spanish Open champion Lawrie are two of the most accurate drivers on the tour and the pair were again safety personified from the tee on a hot, sunny day devoid of wind.
"It is a golf course that suits me," said the Scot. "I generally drive the ball straight and that's definitely key around here."
World number 212 Lawrie made a rip-roaring start to his round, producing three birdies and an eagle in the opening six holes, and his card was without blemish all day.
"It's a course you have to be quite patient on," said the Irishman. "I'm quite a patient person, my wife wouldn't believe that, but I am on the golf course.
"My game is based around plotting my way around. I'm not one of the shorter hitters but I do hit it quite straight."
World number one Rory McIlroy could have done with a straighter approach shot after he took a costly six at the par-five 12th.
He went out of bounds by the narrowest of margins - one inch - and in a fit of belated frustration tossed his club to the ground after his fourth shot.
"I was two-under through seven holes and feeling like I was playing well," said McIlroy after slumping to a 74. "But then I made four bogeys in five holes so it's pretty disappointing.
"You think about the four par-fives on this course and you should be taking advantage of them. Standing on the first tee you're thinking, 'Three or four under par is the worst you should be shooting'."
World number two Luke Donald and third-ranked Lee Westwood were in happier moods after shooting rounds of 68 and 70 respectively.
Former world number one Ernie Els was all smiles after compiling a 68 on the West Course he has redesigned in recent years.
"This place is not a walkover any more," said triple major champion Els. "Guys can go in with a mindset that if they have the right conditions they can make a good score.
"But you have to be mindful of a miss. You're going to get penalised now whereas in the past you could get away with it.
"I played 13 holes perfectly today so maybe tomorrow I can play a couple more holes perfectly."
Els, like Drysdale, needed Lady Luck to be kind to him on the closing hole.
"I don't think there has ever been a human being where I hit it from the tee," laughed the 42-year-old South African. "I think there's a cesspit out there or something.
"Somehow I hit it through the bushes back into play and then a three-iron for my third shot, which is not a lot of fun at a par-five, so I was pleased to make my five in the end."