Speculation over his health had mounted in recent weeks and the 57-year-old had not appeared in public for the past two months.
His officials, led by Bereket Simon, a close friend of Mr Meles and Ethiopia’s communications minister, had denied that he was ill and insisted instead he was “taking a rest” and would be back to work “soon”.
But state television announced early on Tuesday that Mr Meles had died in a hospital abroad – believed to be in Brussels – after complications following treatment for an unspecified illness.
He led the continent’s second-most populous country for more than 20 years, after marching into its capital at the head of a guerrilla army to oust Marxist dictator Mengistu Haile Mariam in 1991.
He became a “donor darling”, whose country was slated to receive £1.3 billion in British aid between 2010 and 2015.
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Bill Clinton called him one of a “new breed of African democrats” and Tony Blair said he was a “visionary leader”.
Recently, Mr Meles ordered his army, among Africa’s largest and best-trained, into neighbouring Somalia to battle Islamist groups said by the West to be harbouring al-Qaeda agents. US spy drones are also based at Ethiopian airports.
His supporters point to average annual economic growth of eight per cent, and say the prime minister used international aid to help drag millions of people from absolute poverty.
But he was increasingly seen as despotic and autocratic, squashing dissent, jailing critical journalists and bloggers and, during the 2005 election, deploying troops who opened fire on protestors, killing as many as 200.
Hailemariam Desalegn, the deputy prime minister, took interim control of the country on Tuesday morning, as stipulated in the constitution, but is not expected to become Mr Meles’ long-term successor.
There is no clear candidate for the job. Ethiopia is ruled by the Ethiopian People’s Revolutionary Demoratic Front, a party formed by Mr Meles that will now decide who takes over.
Discussions could unearth tensions between politicians from different regions. Northerners have run Ethiopia since 1991, and sources suggested that southern candidates would push to succeed Mr Meles.
Ethiopia on Tuesday declared a state of national mourning, but has not fixed a date for a funeral, Mr Bereket told reporters in Addis Ababa, the capital, on Tuesday morning.
The communications minister gave no details of the illness but said Mr Meles had been ill for the past year.
“He has been struggling to be healthy in the last year. One of the best things about him was that he never considered that he was ill and he was up to the job every time, every day, every evening,” he added.
“Illness has never been a hindrance for him, but he has been quite ill for some time.”