Kloppers, who was also director at the Australian company, will be replaced on May 10 after six years at the helm by the company's chief executive of its non-ferrous metals division, Andrew Mackenzie, 56.
In 2010, Kloppers was the head of BHP Billiton when it proposed a US$40-billion deal for Canada's largest producer of potash, a mineral used in fertilizers.
The bid failed to gain the support of the Saskatchewan government, and was eventually blocked by the federal government because it did not pass a net benefit test under the Investment Canada Act based on strategic, fiscal and economic criteria.
BHP Billiton chairman Jac Nasser said Kloppers had been appointed to the role before the global financial crisis.
"Despite an exceptionally difficult environment during his tenure, Marius and his team have delivered for shareholders, significantly outperforming our peers in terms of total shareholder returns," Nasser said in a statement.
"He drove new investments into next generation opportunities including U.S. onshore gas and liquids and created one of the most valuable companies in the world," he added.
Mackenzie brought deep industry knowledge and global management experience to the CEO role, he said.
Mackenzie held senior positions with rival miner Rio Tinto before joining BHP Billiton in 2008.
BHP's retirement announcement came as the company posted a 58 per cent fall in first half profit to $4.24 billion due to lower commodity prices and a weak U.S. dollar.
The company's net profit in the six months to Dec. 31 was down from $9.94 billion in the previous corresponding period.
The result included $1.4 billion in one-off costs from asset sales.
Profit excluding one-off items was $5.7 billion in the six months through December, down 43 per cent from $9.94 billion for the December 2011 half, due to falls in iron ore and other commodity prices in 2012.
Analysts had expected a net profit excluding one-offs of $5.69 billion.