The GBU-43/B Massive Ordnance Air Blast bomb - better known as the "Mother Of All Bombs" - hit IS hideouts in Achin district in eastern Nangarhar province on Thursday.
"As a result of the bombing, key Daesh (IS) hideouts and deep tunnel complex were destroyed and 36 IS fighters were killed," the defence ministry said in a statement.
US President Donald Trump had earlier called the mission "very, very successful".
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The Afghan presidential palace said precautions were taken to avoid civilian casualties.
The huge bomb, delivered via an MC-130 transport plane, has a blast yield equivalent to 11 tons of TNT, and the weapon was originally designed as much to intimidate foes as to clear broad areas.
"The GBU-43/B is the largest non-nuclear bomb ever deployed in combat," Air Force spokesman Colonel Pat Ryder said.
Achin district governor Esmail Shinwari said the bomb landed in the Momand Dara area of Achin district.
Watch: Bomb test in 2003 shows force of GBU-43
"The explosion was the biggest I have ever seen. Towering flames engulfed the area," Shinwari told AFP.
"We don't know anything about the casualties so far, but since it is a Daesh (IS) stronghold we think a lot of Daesh fighters may have been killed."
Nangarhar, which borders Pakistan, is a hotbed of IS militancy. US forces have conducted a number of air strikes on jihadist bases in the area since August last year.
IS, notorious for its reign of terror in Syria and Iraq, has been making inroads into Afghanistan in recent years. It has attracted disaffected members of the Pakistani and Afghan Taliban as well as Uzbek Islamists.
But the group has been steadily losing territory in the face of heavy pressure both from US air strikes and a ground offensive led by Afghan forces.
