Through two rounds, the native of Mosselbay, South Africa, had a tournament record of 12-under 132, three shots better than first-round leader Andrew Coltart of Scotland, who shared the early round lead with two other players.
Oosthuizen made pars at the first three holes, and ended his bogey-free round with seven birdies.
He took sole possession of the lead with a birdie at the par-4 12th hole, and closed with two straight pars.
"It feels nice having a three shot lead after the second round," Oosthuizen said. "I played well and I'm very happy."
Spain's Alvaro Quiros (67) and Australia's Brett Rumford (69) share third place at 8-under 136, with defending champion Adam Scott (70) of Australia tied for 47th place at 1-under 143.
Among those who missed the even par 144 cut were Paul Casey (145) and Darren Clarke (146).