The GBU-43 bomb was dropped on Thursday from a MC-130 aircraft in the Achin district of Nangarhar province, close to the border with Pakistan, said Adam Stump, Pentagon spokesman.
Also known as the "mother of all bombs", the GBU-43 is a 9,797kg GPS-guided munition and was first tested in March 2003, just days before the start of the Iraq war.
The US Central Command (CENTCOM) said the strike was designed to minimise the risk to Afghan and US forces conducting clearing operations in the area.
But the ultra-heavy explosive - equal to 11 tonnes of TNT with a blast radius of 1.6km on each side - could potentially cause many civilian casualties.
The bomb landed in the Momand Dara area of Achin district, according to Esmail Shinwari, district governor.
"The explosion was the biggest I have ever seen. Towering flames engulfed the area," Shinwari told AFP news agency.
"We don't know anything about the casualties so far, but since it is a Daesh [ISIL] stronghold we think a lot of Daesh fighters may have been killed."
General John Nicholson, the head of US and international forces in Afghanistan, said the bomb was used against caves and bunkers used by ISIL in Afghanistan, also known as ISIS-K.
"As ISIS-K losses have mounted, they are using IEDs, bunkers and tunnels to thicken their defence, he said.
"This is the right munition to reduce these obstacles and maintain the momentum of our offensive against ISIS-K".
ISIL's offshoot in Afghanistan, created in 2015, is also known as the Khorasan Province
Mark Kimmitt, a retired brigadier-general in the US army and former deputy assistant secretary of defence, played down the use of the GBU-43, saying it is "just another tool the military has".
"It allows us to go after deeply buried and hardened structures. It's good use against tunnels and it's also good use because it's going to set off IEDs in the area," he told Al Jazeera.
Kimmitt said it was not at all certain that "political authorities" were informed of the raid before it was carried out.
"Although the size of the bomb was a bit larger than normal, it was a routine military mission against a routine military target," he said.
The White House would not confirm whether or not President Donald Trump had authorised the use of the bomb.
"Everybody knows exactly what happened and what I do is I authorise my military," Trump told reporters.
"We have the greatest military in the world and they've done their job as usual. So, we have given them total authorisation."
US officials say intelligence suggests ISIL is based overwhelmingly in Nangarhar and neighbouring Kunar province, among tens of thousands of civilians.
Estimates of ISIL's strength in Afghanistan vary.
US officials have said they believe the group has only 700 fighters, but Afghan officials estimate there are closer to 1,500 in the country.
Western and Afghan security officials believe fighters frequently switch allegiances between armed groups, making it difficult to know who is to blame for violence.
Peter Galbraith, a former US diplomat and former UN deputy special representative for Afghanistan, said ISIL would have to be targeted in different locations for the US military strategy to succeed.
"ISIL doesn't concentrate its forces ... so you have to target it in many different places," he told Al Jazeera.
He said conditions for military operations in ISIL's Syrian and Iraqi strongholds, Raqqa and Mosul, are different, as they are urban areas with civilian populations.
"A bomb of this magnitude could cause a lot of collateral damage," Galbraith said.
"But when you're using it in a remote, rural part of Nangarhar province in Afghanistan, you presumably can have some confidence that you'll not have civilian casualties, or at least not many of them."