Meles died Monday just before midnight after contracting an infection, state TV said. Hailemariam Desalegn, who was appointed deputy prime minister and minister of foreign affairs in 2010, is now in charge of the Cabinet, state TV said.
Meles hadn't been seen in public for about two months. In mid-July, after Meles did not attend a meeting of heads of state of the African Union in Addis Ababa, Ethiopia's capital, speculation increased that his health problems were serious. Ethiopian officials gave no details and said the prime minister was in "very good" health and would return to the office soon, but international officials said quietly it was unlikely he would recover.
State TV on Tuesday showed pictures of Meles as classical music played in the background.
Born on May 8, 1955, Meles became president in 1991 after helping to oust Mengistu Haile Mariam's Communist military junta, which was responsible for hundreds of thousands of Ethiopian deaths. Meles became prime minister in 1995, a position that is both the head of the federal government and armed forces.
The US has long viewed Meles as a strong security partner and has given hundreds of millions of dollars in aid over the years. US military drones that patrol East Africa - especially over Somalia - are stationed in Ethiopia. The US goal for Somalia - a stable government free of radical Islamists - is in line with Ethiopia's hopes.
Though a US ally, Ethiopia has long been criticized by human rights groups for the government's strict control, and Meles' legacy is likely to be mixed: positive on the economic development side and negative on the human rights side, said Leslie Lefkow, the deputy director for Human Rights Watch in Africa.
Meles brought Ethiopia out of a hugely difficult period following Mengistu's rule and made important economic progress, she said, but the ruling party has been too focused on building its own authority in recent years instead of building up government institutions.
"I think on the human rights side his legacy will be much more questionable. 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," Lefkow said.
During Meles' election win in 2005, when it appeared the opposition was likely to make gains, Meles tightened security across the country, and on the night of the election he declared a state of emergency, outlawing any public gathering as his ruling party claimed a majority win. Opposition members accused Meles of rigging the election, and demonstrations broke out. Security forces moved in, killing hundreds of people and jailing thousands.
In 2010 Meles won another five years in office while receiving a reported 99 percent of the vote. Meles is the longtime chairman of the Tigray People's Liberation Front and has always identified strongly with his party.
"I cannot separate my achievements from what can be considered as the achievements of the ruling party. Whatever achievement there might have been, it does not exist independent of that party," Meles once said when asked what he thought would be his legacy.
Under Meles, Ethiopia saw strong gains in the education sector with the construction of new schools and universities. Women gained more rights. And in the mid-2000s Ethiopia saw strong economic growth, which won Meles international praise. The International Monetary Fund in 2008 said Ethiopia's economy had grown faster than any non-oil exporting country in sub-Saharan Africa.
Despite those gains, Ethiopia remains heavily dependent on agriculture, which accounts for 85 percent of the country's employment. Per capita income is only about $1,000, or roughly $3 a day.
Though he won accolades for economic progress, human rights groups have long denounced Meles' government for its use of arbitrary detention, torture, and surveillance of opposition members inside Ethiopia. The ONLF, an opposition group that mostly consists of ethnic Somalis, has openly clashed with the government, including in 2007 when Ethiopia sent troops to Somalia to fight al-Shabab militants.
At the end of 2006, Somalia's UN-backed government asked Ethiopia to send troops into Somalia to try to put down an Islamist insurgency. Ethiopian troops moved into the country and captured Mogadishu, but the Somali population rebelled against what it saw as an occupation and Ethiopian forces withdrew in 2009.
Meles grew up in the northern town of Adwa, where his father had 13 siblings from multiple women. He moved to the capital, Addis Ababa, on a scholarship after completing an eight-year elementary education in just five.
Meles is survived by his wife, Azeb Mesfin, a member of parliament, with whom he had three children.
State TV said funeral arrangements would be announced soon.