He had been known as a critical figure of successive governments.
Mr Mesfin founded the Ethiopian Human Rights Council, a rights watchdog.
He joined the opposition Coalition for Unity and Democracy (CUD) during the disputed election in 2005.
The CUD managed to win all but one seat in Addis Ababa and an unprecedentedly high number of seats in federal and regional parliaments. But the party claimed it had won even more seats than the number acknowledged by the electoral board.
Following the dispute, senior leaders of the party including Mr Mesfin were accused by the government of unconstitutional attempts at power grab and were jailed.
Mr Mesfin left the party later and described his involvement in party politics as a mistake, saying that he was more comfortable in critiquing those in power than seeking to be in power.
A geography professor by training, he wrote more than a dozen books on politics, history and culture. He was also a prolific commentator on newspapers and later on social media.
Prime Minister Abiy Ahmed has described him as “a champion of peaceful struggle” and someone “who stood only for what he believed in”.
A Twitter account, EthioTube, shared a photo of Mr Mesfin:
— EthioTube (@EthioTube) September 30, 2020