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 returning to 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.
American Kitayama’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.
Ernie Els, another home favourite, is also at five under par.
Oosthuizen said: “Any time, anywhere, nine under is always going to feel nice. 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.”
Sheffield’s Joe Dean, playing on one of his few exemptions after missing out on full playing privileges at Q School last month, shot a level-par 71 on the Bushwillow course.
Leeds’ Daniel Gavins is three shots further back after a 74 over the same course.