The prime minister hadn't been seen in public for about two months before his death. His illness was disclosed after he failed to attend an important African Union summit in the Ethiopian capital of Addis Ababa last month.
The nature of his illness hadn't been disclosed.
State television announced that he died just before midnight Monday after contracting an infection while in the hospital.
"Prime Minister Zenawi suddenly passed away last night. Meles was recovering in a hospital overseas for the past two months but died of a sudden infection at 11:40 p.m.," the statement said.
In recent weeks, authorities had downplayed Meles' illness as minor, despite rumors that he was in a critical condition in a hospital in Belgium.
A government spokesman, Bereket Simon, recently dismissed reports that Meles was seriously ill, saying he was recuperating well. Bereket told the Agence France-Presse news service Tuesday that Zenawi "had been recuperating well but suddenly something happened and he had to be rushed to the ICU [intensive care unit] and they couldn't keep him alive."
Deputy Prime Minister Hailemariam Desalegn takes over as acting prime minister, state television said.
As prime minister -- head of the government and military -- Meles ruled his country with an increasingly authoritarian hand. Under his leadership, opposition figures and journalists were jailed or killed. In 2005, police shot and killed 200 people who were protesting against election results that they claimed were rigged. Five years later, Human Rights Watch described Ethiopia under Meles as effectively a single-party state, after his government's "five-year strategy of systematically closing down space for political dissent and independent criticism."
Meles' death raises questions about stability in a region seen by Washington as a front line in the war against terror. Despite his poor human rights record, Meles was a close U.S. counter-terrorism ally, a bulwark against Al Qaeda in the volatile Horn of Africa.
The U.S. has given Ethiopia millions of dollars in aid, and houses a drone base in the country.
In 2006, Ethiopia invaded neighboring Somalia with U.S. support to topple the Islamic Courts Union, a religious alliance that had taken power in the country, on U.S. concerns that some figures in the group were members of Al Qaeda. Ethiopia withdrew in 2009.
The invasion left Al Shabab, an Al Qaeda-linked militia in control of much of the country, but last year Ethiopian troops moved back into Somalia, as part of an offensive against Al Shabab involving troops from Uganda, Kenya and Burundi.
Meles, a former rebel guerrilla fighter, took power after overthrowing the communist military junta of Mengistu Haile Mariam in 1991.
He was the third African leader to die in office this year. Longtime Malawian leader Bingu wa Matharika collapsed and died suddenly in April, with authorities initially suppressing news of his death while a power struggle unfolded behind the scenes. Last month, Ghanaian President John Atta Mills died at 68, months before he was due to seek reelection.
Meles won praise in the West for stabilizing his country, ushering in years of double-digit economic growth and improving education.
"I think the human rights side of his legacy will be much more questionable," Leslie Lefkow, deputy director of Human Rights Watch in Africa told the Associated Press. "The country remains under a very tightly controlled one-party rule and this will be the challenge for the new leadership, to take advantage of the opportunity that his death presents in terms of bringing Ethiopia into a more human rights-friendly, reform-minded style of leadership."
Meles is survived by his wife, Azeb Mesfin, a member of parliament, and three children, Semhal, Senay and Marda.
-- Robyn Dixon
Photo: Ethiopian Prime Minister Meles Zenawi speaks during the 20th World Economic Forum on Africa. Credit: Khalfan Said / Associated Press