It is not yet clear what caused the explosion in the port area of the city. Video posted online showed a large mushroom cloud and destroyed buildings.
The blast killed at least 50 people and injured more than 2,500 others, the health minister says.
Hospitals are said to be overwhelmed and many buildings have been destroyed.
Lebanon's internal security chief said the blast happened in an area housing highly explosive materials. Lebanon's National News Agency reported a fire breaking out at what it called an explosives depot at the port before the explosion.
Windows were broken and buildings shaken for miles around the explosion.