Forbes magazine has compiled the list taking into account the total amount of money actually given and not just pledged by the philanthropists.
The Gates couple gave a total of USD 1.9 billion in 2012, which is 2.6 per cent of their wealth, bringing their total lifetime givings to USD 28 billion.
The Microsoft founder is helping eliminate polio and combat malaria, including in India, through the Bill & Melinda Gates Foundation.
Some of his big recipients include the World Health Organization, the Medicines for Malaria Venture and the United Negro College Fund, Forbes said.
Of the top Philanthropic 50, 40 are also on the Forbes Billionaires list, led by Bill and Melinda Gates and Warren Buffett who are also founders of the Giving Pledge. Each put almost USD 2 billion towards philanthropic work in 2012 - the year's only ten-digit givers - with Gates edging Buffett by a mere USD 35 million.
The Forbes list also attempts to estimate lifetime giving, with the Gates couple and Buffett both giving away at least USD 25 billion apiece through the end of last year.
Berkshire Hathaway CEO Buffett is second on the list of the top 50 Philanthropists, giving away a total of USD 1.87 billion last year, which is 3.2 per cent of his wealth.
Business tycoon George Soros is on the number three spot with total givings of USD 763 million. In 2012, Soros gave USD 285 million to governance and accountability programmes and nearly USD 250 million to human rights initiatives.
Facebook founder Mark Zuckerberg is on the fourth spot with a total contribution of USD 519 million in 2012, nearly 2.2 per cent of his wealth.
Zuckerberg donated nearly half a billion dollars in Facebook stock to the Silicon Valley Community Foundation in 2012. He also gave USD 20 million of the USD 100 million pledge he made to Newark schools in 2010.
In order to separate words and actual deeds, Forbes worked with the Philanthropic Research Institute to rank which Americans gave the most in the last calendar year - not money pledged - but actual cash deployed in the field.
"Givers now want to see an impact while they're still alive," says PRI founder R J Shook.
Buffett has committed that his entire Berkshire Hathaway holding, upwards of USD 58 billion, will be donated before or at his death, with a further mandate that it will be put to use within ten years of the latter.