The home hero has a Claret Jug and seven other European Tour wins to his name but he has never won his home Open and is teeing it up at the event for the first time since 2010.
Starting on the shorter but narrower of the two courses being used this week, he was bogey-free in getting to nine under, one shot clear of last week's winner in Mauritius Kurt Kitayama - who played the Firethorn Course - and Zambia's Madalitso Muthiya.
The American's 63 was the lowest round of the day on the Firethorn and left him in a commanding position heading into round two.
South African Zander Lombard also played the longer course and he was seven under, a shot clear of countryman Tyrone Ferreira, England's Matt Wallace and Zimbabwean Mark Williams.
The Firethorn - which will play host to the full field after the cut - will provide Oosthuizen with a very different challenge on Friday and the 36 year old will be rebooting for day two.
“Any time, anywhere, nine under is always going to feel nice,” he said. “It was one of those rounds where you don’t really look at any scoreboard or your card, you just play.
“I drove it really well and gave myself good opportunities to hit it close and I’m putting nicely, so it was just birdie after birdie.
“There’s a long way to go. I’ve got one of the courses out of the way so now I just focus on the main course for the week and it feels like a new tournament starting tomorrow for me.”
Wallace shared the early lead at four under with gains on the first, second, third and fifth but dropped a shot on the eighth to turn in 32.
Oosthuizen did the same with birdies on the first, fifth and seventh and the playing partners then went head-to-head, each making a hat-trick of birdies from the tenth.
They both holed six-footers on the tenth and made the most of the par-five 12th, with Oosthuizen hitting an approach to tap-in range and Wallace holing a ten-footer on the 11th.
It was all change on the 14th as Oosthuizen holed an eight-footer and Wallace dropped a shot to make it a two-stroke lead.
An 18-foot right-to-lefter on the 16th then put Oosthuizen three ahead and he briefly led by four after a birdie at the par-five 17th before Wallace followed him in.
Muthiya made a flying start with birdies on the first, second and third and further gains on the fifth, sixth and ninth meant he had joined Wallace in second. He got on the 12th in two for another birdie and was within one with an eighth of the day from ten feet on the 15th.
Kitayama holed a long putt on the first and chipped in at the third with gains on his next two holes moving him to four under.
Eight pars followed but he got on the green at the par-five 14th in two for an eagle and put his tee-shot on the par-three next to eight feet for a birdie, before closing with another gain from 12 feet.
Qualifying School co-winner Lombard started with a bogey but hit back in style with birdies on the third, fifth, sixth, seventh, 12th, 14th, 16th and 17th.
Ferreira was off the pace when he turned in 33 with birdies on the first and fifth but picked up shots on the 11th, 12th, 17th and last.
Williams sandwiched birdies on the fifth, eighth, tenth, 11th, 12th and 14th with bogeys on the second and 15th, before making and eagle on the par-five 17th.
Four-time Major winner Ernie Els has won this event five times and he was at five under alongside fellow South Africans Branden Grace, Jbe Kruger, David McIntyre and Jake Roos, Germans Max Schmitt and Marcel Siem, England's Tom Murray and Brazilian Adilson da Silva.