Tunisian Prime Minister Youssef Chahed on Wednedsay fired Interior Minister Lotfi Brahem, a government statement said, after one of the worst migrant boat accidents in recent years.
The boat packed with some 180 migrants sank on Sunday off Tunisia's coast. The death toll has risen to at least 68, with dozens still missing.
The statement gave no reason for the sacking, but a government official, speaking on condition of anonymity, said: "Chahed fired the interior minister for failing to stop the boat and illegal boat migration in general."
Earlier on Wednesday Chaded also fired 10 security officials for failing to stop the boat.
Brahem will be replaced by Justice Minister Gazi Jribi, it said.
Most of the people on board the boat that sank on Sunday were Tunisians trying to escape unemployment and an economic crisis that has gripped the North African country since the toppling of autocrat Zine El-Abidine Ben Ali in 2011.
Hundreds of people protested in the southern towns of Madenine, Tataouine and El Hamma on Tuesday evening against the poor economic conditions, residents said.
Human traffickers have increasingly moved their operations to Tunisia since a crackdown by the coastguard in neighbouring Libya.
Tunisia stopped about 6,000 migrants leaving its coast for Europe in the first five months of the year - a sharp increase from the few hundred prevented in the same period last year, an interior ministry official said.
This year up to May 2, a total of 1,910 Tunisian migrants reached Italy, including 39 women and 307 minors - 293 of whom were unaccompanied - compared to only 231 for the same period in 2017, according to the UN migrant agency IOM.
Overall, the number of migrants reaching Italy has fallen sharply since last July, when a major smuggling group in the Libyan coastal city of Sabratha struck a deal to halt departures under Italian pressure and was then forced out in clashes.
Libya's EU-backed coastguard has also returned more migrants to that country after intercepting them at sea.