Information Minister Abdel Samad, Justice Minister Marie-Claude Najm, Finance Minister Ghazi Wazni, and Environment Minister Damianos Kattar announced their resignations early in the Monday morning. Nine lawmakers also resigned from office.
According to the Lebanese legislature, if seven ministers of the 20 Cabinet ministers resign, a new government must be formed.
Over the last months, the country has been going through its worst financial crisis in decades. The government, which is backed by the military group Hezbollah, was struggling to develop reforms to revive the country's economy.
Thousands of people have been mobilizing in Beirut after the blast that left 160 dead and at least 6,000 injured, to demand the resignation of President Michel Aoun.