Speaking to people in a live televised address on Monday, Diab first blamed the explosion on mismanagement resulting from “endemic corruption” in the country.
"Today we follow the will of the people in their demand to hold accountable those responsible for the disaster that has been in hiding for seven years, and their desire for real change," he said, adding, "In the face of this reality ... I am announcing today the resignation of this government."
"May God save Lebanon, may God save Lebanon, may God save Lebanon.”
Elsewhere in his remarks, Diab slammed certain corrupt political actors for undermining his government's efforts by distorting truth.
He said his government "tried to create change to meet demands of the Lebanese people, adding, "we are with the people in calling for trying those responsible for this crime."
Diab also denounced those who are trying to take advantage of the Beirut blast for their own political gain.
According to a televised announcement later on Monday, Lebanese President Michel Aoun has accepted the resignation of the prime minister's government, asking it to stay on in a caretaker capacity until a new cabinet is formed.
After months of a power vacuum in the small Mediterranean country, Diab's cabinet formed in January to combat alleged corruption and mismanagement, and to revive Lebanon’s collapsed economy.
Before Diab announced the government's resignation, four cabinet ministers had already quit their posts.