Greene was born in 1954 in Worcester, Massachusetts to a working class Jewish family. His Father ran a Business selling textile mill machinery. His mother was a Hebrew school instructor who taught Greene to "save his pennies, look for value, and never pay Retail." His family moved to Florida in 1970 after his Father lost his Business. In Florida, his Father worked refilling vending machines and his mother worked as a waitress.

Greene worked many jobs to put himself through college at Johns Hopkins University, graduating in three years with a B.A. in economics and sociology. Later he attended Harvard Business School, where he earned his Master of Business Administration (MBA) degree in 1977. Greene lived in Southern California in the 1980s and 1990s and ran in the 1982 Republican primary for the 23rd Congressional District race. Greene lost the primary to David Armor who then lost to incumbent Democrat Anthony C. Beilenson.

Greene began investing in real estate while in Business school, and built a successful real estate Business from being a mere busboy at the Breakers Hotel in Palm Beach. In mid-2006, Greene, worried about the possible collapse of the real estate market, spoke with John Paulson, a fellow investor who discussed with Greene his investing strategy. They agreed that the real estate market was unstable and a bubble might be forming in housing. After the meeting, Greene engaged in a similar investing strategy to that of Paulson, which involved a series of unconventional Investments trading credit default swaps. The return on Greene’s Investments ultimately saved his Business, and put him on Forbes 400 list.

In 2007, Greene married Chinese Australian real estate executive Mei Sze Chan, who is twenty years his junior in age. Chan was an ethnic Chinese refugee from Malaysia who first fled to Australia with her family before heading to New York City after college. In 2009, she gave birth to their first child, Malcolm. Greene and his wife now have three sons and live in Palm Beach. Greene was quoted as saying, “I just wish I had met Mei Sze 20 years ago."

On April 30, 2010, Greene announced his intention to run as a Democrat for the United States Senate seat held by George LeMieux, saying, "I am an outsider, the only candidate who isn’t a career Politician. I’ve succeeded in the real world of hard work – the others have only succeeded at running for political office after office." Greene stated he would refuse campaign contributions from special interests, and would limit individual donations to $100. His platform focused on economic reforms and job creation. Greene introduced his story and his campaign with a sixty-second video on YouTube. Greene's campaign was endorsed by the Tallahassee Democrat's editorial board. The board commended Greene for his "edge and an Energy that make him want to push beyond the usual talking points", remarking, "we like the toughness he would bring to the office".

In February 2011 Greene became a signatory of The Giving Pledge.

While attending the World Economic Forum in Davos, Switzerland, it was reported that Greene made the following statement: "America’s lifestyle expectations are far too high and need to be adjusted so we have less things and a smaller, better existence. We need to reinvent our whole system of life". Greene denies making that statement. Greene was met with criticism after it came out that he had flown his wife, children and two nannies on a private jet plane to Davos for the week.