The 2010 Champion had been peerless over the first two days at Royal St George's Golf Club and made serene progress over the first ten holes of round three despite three time Major Champion Jordan Spieth applying the pressure.
The South African had to dig deep over the back nine to get to 12 under and as Spieth faltered down the stretch, American Collin Morikawa carded a 68 to emerge as Oosthuizen's closest challenger.
That left the mouth watering prospect of the men second and third in the Race to Dubai Rankings in Partnership with Rolex going head to head in search of their second Major wins, with American Spieth third at nine under.
Oosthuizen has already finished second in two Majors this season to take his career tally of runner-up finishes in golf's biggest events to six but has shown no signs of scar tissue on the English coast.
The nine time European Tour winner has looked the form man all week in Sandwich and should he complete the job on Sunday, he will become the first wire to wire Major winner since Dustin Johnson at the 2020 Masters Tournament and the first at The Open since Rory McIlroy in 2014.
“I was definitely not swinging it freely today, I was all over the place with iron shots and it felt like I kept it together at the end there,” he said.
“I’m very excited, it is a great position. I need to play well tomorrow and see if I can get rid of those loose swings.
"You need to believe that you can lift the trophy as well and if you think about it beforehand that you might win this championship, I think that's great, and you have to believe you can do it.
"Finishing second isn't great, so I will play my heart out tomorrow and see if I can lift the Claret Jug again."
The 38-year-old missed good chances on the first and second to extend his two shot overnight lead and while Spieth played a wonderful shot from the rough and got a bit of luck on the second to leave himself three feet to get to nine under, Morikawa dropped a shot after finding sand off the tee.
Finishing second isn't great, so I will play my heart out tomorrow and see if I can lift the Claret Jug again
Spieth was within one when he holed from nearly 30 feet on the fourth but he failed to get up and down from over the back of the fifth before putting his tee shot to six feet at the sixth to get back to double figures.
A two putt birdie from long range on the seventh moved Spieth into a share of the lead but Oosthuizen edged back ahead on the same hole with a two putt of his own.
Morikawa had made a second bogey of the day after finding two nasty stances on the fifth but he too made a two putt birdie on the seventh and then rolled in a 30 footer on the eighth to get back to nine under.
The leader was two ahead as he made a 13 footer on the ninth to turn in 33 but Spieth hit back from similar range on the tenth and the duo were pulling away from the rest.
But they gave the field some hope as they both bogeyed the 242 yard par three 11th, Spieth finding sand off the tee and Oosthuizen failing to get up and down after rolling off the putting surface.
Spieth was in a share of the lead as Oosthuizen dropped a shot on the 13th after finding rough off the tee, and Morikawa joined him as he holed another 30 footer and then made a second two putt birdie of the day on the par five 14th.
Oosthuizen had to battle for par on the 14th and 15th but he led on his own after a stunning tee shot to eight feet on the 16th, with Spieth falling back after rolling off the front of the 17th green and then three putting the last in a 69.
Conners made four birdies in five holes from the tenth in a 66, while Scheffler bogeyed the second but birdied the seventh and last in a 69.
U.S. Open Champion Rahm was level par after 13 holes but birdies on the 14th and 17th kept the Spaniard in touch, with Hughes also carding a 68 and Frittelli signing for a 70.