The ministry says no civilians were affected by the explosion.
The bomb was dropped on a tunnel complex used by so-called Islamic State in Nangarhar province.
Former Afghan President Hamid Karzai condemned the attack as an inhuman and most brutal misuse of his country.
The GBU-43B, a 21,000-pound conventional bomb, was deployed in Nangarhar Province close to the Afghanistan/Pakistan border.
By comparison, each Tomahawk cruise missile launched at a Syrian military air base last week weighed 1,000 pounds each.
Pentagon spokesman Adam Stump said the bomb had been brought to Afghanistan "some time ago" for potential use.
The bomb explodes in the air, creating air pressure that can make tunnels and other structures collapse.
It can be used at the start of an offensive to soften up the enemy, weakening both its infrastructure and morale.
"As [ISIS'] losses have mounted, they are using IEDs, bunkers and tunnels to thicken their defense," Gen. John Nicholson, commander of U.S. forces in Afghanistan, said in a statement. "This is the right munition to reduce these obstacles and maintain the momentum of our offensive against [ISIS]."
President Trump told media Thursday afternoon that "this was another successful mission" and he gave the military total authorization.