O'Keefe replaces injured paceman Peter Siddle in the only change to the team that trounced the Windies by 177 runs in Melbourne to retain the Frank Worrell Trophy.
Siddle has not recovered from an ankle injury he sustained in the Melbourne Test and was not 100 percent fit for Sunday's final Test, skipper Steve Smith said.
"He (Siddle) felt it wasn't best for him to come into this Test match the way he is at the moment," Smith told reporters at the ground.
Smith said Australia had gone with the twin spin option as he expected the Sydney Cricket Ground pitch to turn.
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"The wicket looks dry so I think it'll take some spin. Peter Siddle is still a little bit sore. He'll have a rest for a couple of weeks and hopefully get himself right for (February's tour of) New Zealand."
It will be the first time in a decade that Australia will play two specialist spin bowlers at home, after leg-spinners Shane Warne and Stuart MacGill bowled together against South Africa in Sydney in 2006.
"I enjoy playing with Nathan, he is a humble, lovely guy who I admire a lot and fingers crossed we can get that opportunity again," O'Keefe said.
"There are a couple of situations we have bowled the majority of the overs and enjoyed going each side of the bat."
O'Keefe, 31, made one Test appearance against Pakistan in Dubai over a year ago, claiming four wickets in a 221-run loss.
He was named in Australia's Test squad to travel to Bangladesh in October last year before the tour was cancelled amid safety concerns.
Allrounder Mitchell Marsh will provide the third seamer's spot behind opening bowlers Josh Hazlewood and James Pattinson in the Australia pace attack.
Australia - David Warner, Joe Burns, Usman Khawaja, Steve Smith (capt), Adam Voges, Mitch Marsh, Peter Nevill, Steve O'Keefe, James Pattinson, Josh Hazlewood, Nathan Lyon.