Wickremanayake, 83, who also held many key ministerial positions since 1970, was ailing for sometime and breathed his last this morning, his family said.
He was admitted to the Intensive Care Unit of a leading private hospital on December 21.
Wickremanayake served twice as the Island nation's premier first from 2000 to 2001 and then from 2005 to 2010.
He was appointed prime minister by former Sri Lankan president Mahinda Rajapaksa on November 21, 2005.
It was Wickremanayake who paved the way for Rajapaksa to emerge as the next leader of the Sri Lanka Freedom Party (SLFP). He resigned from his position as the leader of the main opposition in 2002 to make way for Rajapaksa to become the leader of the opposition.
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In his previous stint as prime minister, Wickremanayake succeeded prime minister Sirimavo Bandaranaike who had resigned at the age of 84.
A host of political leaders cutting across party lines condoled the death of Wickremanayake.
"Veteran Politician Ratnasiri Wickremanayake was loved by his people for many decades. My condolences are with his loved ones and followers," President Maithripala Sirisena tweeted.
Rajapaksa also tweeted his condolences.
"Deeply saddened by the death of former Sri Lankan PM & veteran politician Ratnasiri Wickremanayake. My condolences to his family," Rajapaksa said in a tweet.
In 1970, he was appointed Deputy Minister, Justice and went on to be the General Secretary of SLFP in 1977.
In the 1994 General Election, he won the Kalutara District seat and was appointed as the Minister of Public Administration, Home Affairs and Plantation Industries and the Leader of the House in President Chandrika Kumaranatunge's Cabinet.
His son Vidura Wickremanayake is also a member of the parliament.