The German powerhouse sprinted to the line to equal former champion Robbie McEwen's record of 12 wins at the race around the Adelaide region.
Greipel, like McEwen a previous champion, held off the challenges of Frenchman Arnaud Demare of FDJ and home hope Mark Renshaw of Blanco for the win.
Greipel's Lotto team had controlled the peloton for much of the day on the 135-kilometre journey from Prospect to Lobethal in South Australia.
"We expected more attacks," Greipel said. "The team did an awesome job again. It was hard to control and keep me up the front but the team did an awesome job."
Astana rider Simone Ponzi crossed the line in fourth, with Garmin's Steele Von Hoff fifth.
After only five kilometers Jordan Kerby attacked and the young Australian opened up a gap of 7:30 but Lotto Belisol and Argos-Shimano reeled him before a counter-attack from Jerome Pineau.
But the Frenchman's audacious bid for an unlikely victory failed as the peloton reeled him in.
It was left to sprint king Greipel to outpace his rivals, and take an early lead of the overall standings ahead of Demare and Renshaw.
Another Australian, Simon Gerrans of Orica, lies fourth in the fledgling general classification, with Belgium's Philippe Gilbert of BNC Racing fifth.
Stage two of six sees the peloton travel 116.5km from the Adelaide Hills town of Mount Barker to Rostrevor.