Sharpe previously picked up the award, which is voted for by all Australian-based professionals, in 2003 and 2006.
The 33-year-old enjoyed a remarkable year in 2011 as he overtook Gregan as the most-capped player in Super Rugby history.
He broke the Forces' long-standing consecutive appearance record when played his 53rd straight match and became the fourth most-capped Wallaby when he faced Wales in Cardiff earlier this month.
Sharpe has now won 101 caps for his country and remains a contender for the 2013 Lions tour when Britain and Ireland's elite head Down Under in less than 18 months time.
The Force skipper, who has also captained the Wallabies, beat off stiff competition for the RUPA honour from clubmate David Pocock, Melbourne Rebels full back Mark Gerrard and the Brumbies' Pat McCabe and Stephen Moore.
In September, Wallaby fullback Kurtley Beale was awarded the John Eales Medal after winning a player-poll to find the country's Player of the Year while Reds' scrum-half Will Genia won the vote to be named Australia's Super Rugby Player of the Year in June.
Previous RUPA Medal for Excellence winners
2001 - George Gregan
2002 - Nathan Sharpe
2003 - Brendan Cannon
2004 - George Gregan
2005 - Nathan Sharpe
2006 - George Gregan
2007 - George Smith
2008 - George Smith
2009 - Berrick Barnes
2010 - David Pocock