Tsvangirai led the opposition party since 1999, and was due to stand in presidential elections this year.
His political nemesis, Robert Mugabe, was removed from power in a military takeover in November.
Tsvangirai had been expected to lead an alliance of opposition parties in presidential and parliamentary polls in July.
His death is likely to heighten power squabbles that erupted within the party while he was receiving medical treatment in South Africa.
One of the party’s vice presidents, Elias Mudzuri, said the Movement for Democratic Change had lost an icon and a fighter for democracy.
On social media, Zimbabweans expressed sorrow, with some hailing Tsvangirai as a hero.
The MDC president had been synonymous with the fight for democracy since his party’s formation nearly 20 years ago.
His arch rival during that entire period was Robert Mugabe.
Tsvangirai never managed to attain his dream of leading Zimbabwe, and eventually it was Mugabe’s own party who removed the aging president from power in a military takeover last year.
Last month, as his battle against colon cancer intensified, Tsvangirai had hinted at retiring from politics, and handing over leadership of the party to younger officials.
Many are wondering what will happen to his party now that its strong figurehead is no more.