The bomb, known officially as a GBU-43B, or Massive Ordnance Air Blast weapon, unleashes 11 tons of explosives.
When it was developed in the early 2000s, the Pentagon did a formal review of legal justification for its combat use.
The US military headquarters in Kabul said in a statement that the bomb was dropped at 7.32pm local time on a tunnel complex in the Achin district of Nangarhar province, where the Afghan affiliate of the ISIS group has been operating.
The target was close to the Pakistani border.
Adam Stump, a Pentagon spokesman, said the bomb was dropped from a US Air Force MC-130 transport, which he said had been brought to Afghanistan "some time ago" for potential use.
Army General John W Nicholson, commander of US forces in Afghanistan, said the strike was designed to minimise the risk to Afghan and US forces conducting clearing operations in the Achin area "while maximising the destruction" of IS fighters and facilities.
He said IS has been using improvised explosive devices, bunkers and tunnels to strengthen its defences.
"This is the right munition to reduce these obstacles and maintain the momentum of our offensive against Isis-K," he added, using the US military's acronym for the IS affiliate.
White House spokesman Sean Spicer said ISIS fighters had used the tunnels and caves in Achin to manoeuvre freely.
"The United States takes the fight against Isis very seriously and in order to defeat the group we must deny them operational space, which we did," Mr Spicer said.