Thriving in overcast and blustery conditions, the South African carded a bogey-free round, which included two birdies at his first two holes, after teeing off at the tenth.
The 2010 British Open champion was joined at the top of the leaderboard by Spain’s Pablo Larrazabal, who posted four birdies in his first nine holes.
Belgium’s Nicolas Colsaerts, England’s Andrew Johnston and Sweden’s Bjorn Akesson formed a trio one shot further back.
“I like playing in the desert,” the 33-year-old Oosthuizen said.
“I always play well around here, and just like the golf course. Like I said, I like the type of shot-making, grainy greens. It brings back a lot of good memories.”
His card included back-to-back birdies at the ninth — the longest hole on the course, a 639-yard par 5 — 10th and 11th holes.
Despite his self-professed love of windy conditions, Oosthuizen, one of the pre-tournament favourites, admitted that there could be “horrible winds” during the rest of the week.
At the start of 2011 and 2012, Oosthuizen won back-to-back Africa Opens. And in 2013 and 2014 he recorded consecutive wins at the Volvo Golf Champions, all season-opening tournaments.
A “very happy” Larrazabal, who has won a tournament on the European Tour in each of the last two seasons, made a similar start to Oosthuizen, birdying his first two holes also, after teeing off at the first.
He followed that up with birdies on the sixth and ninth to go out in just 32.
Like Oosthuizen, he did not card a bogey all round and missed only one green all day, at the par three 13th.
It looked like there would be a three-way lead at the top but Akesson bogied his penultimate hole, a four at the par three eighth.
Another who threatened the top of the leader board was Englishman Callum Shinkwin.
The 21-year-old, starting at the tenth, went out in just 30, carding six birdies in the first nine.
He could not maintain that pace though and took a double bogey at the second and another at the ninth, but remained upbeat afterwards.
“I’m pleased,” he told reporters. “I played nicely. I holed a few putts, which is a change, so I was happy with that.”
It was a big day for the Shinkwin family, with his boxing cousin, Miles, announcing on Wednesday he will fight for the vacant British light-heavyweight title next month.
Defending champion Branden Grace, seeking to become the first player in the Qatar Masters 17-year history to win back-to-back titles, carded a two under round of 70.
That was the same score as the 2013 champion Sergio Garcia.
The first person to win in Qatar, Scotland’s Paul Lawrie, fared better with a five under par 67.
