Ashton Carter, the outgoing US defence secretary, said initial estimates suggested more than 80 fighters were killed.
“They were external plotters who were actively planning operations against our allies in Europe,” he said.
“They may also have been connected with some attacks that have already occurred.”
Mr Carter, speaking in his last press briefing before Donald Trump’s inauguration, said: “These were critically important strikes in our campaign and to destroy Isis not just in Iraq and Syria, but wherever it emerges."
He said he was confident that his successor would continue American efforts to “deliver Isil (Isis) the lasting defeat it deserves”.
More than 100 munitions were dropped by two US B-2 stealth bombers that were flown all the way from a base in Missouri for the mission.
Journalists were shown surveillance footage from the air of Isis fighters on the ground, moving shells and rockets between vehicles covered in desert camouflage.
Peter Cook, the Pentagon press secretary, said the operation was carried out around 25 miles southwest of the group’s former stronghold of Sirte on Wednesday night.
Militants had gathered there after fleeing the US-backed assault that drove them out of the coastal city “in order to reorganise”, he added.
“They posed a security threat to Libya, the region, and US national interests,” Mr Cook said.
“While we are still evaluating the results of the strikes, the initial assessment indicates they were successful.
“We are committed to maintaining pressure on Isil (Isis) and preventing them from establishing safe haven.”
The mission was authorised directly by Barack Obama in his last days as President, having given military support to Libyan militas’ effort to retake Sirte last year.
His successor has been unclear on his position over Libya, hitting out at America’s support for British and French-led efforts to oust Muammar Gaddafi.
“We would be so much better off if Gaddafi would be in charge right now,” Donald Trump said on the campaign trail last year.
But in 2011 he claimed he would have authorised strikes to “knock this guy out very quickly…to save lives”.
The US carried out several rounds of air strikes targeting Isis in Libya since receiving a request from the country last year.
Two Serbian embassy employees being held hostage by the militants were killed by an American bombing raid near Sabratha in February.
In pictures: Isis' Libyan stronghold of Sirte
In pictures: Isis' Libyan stronghold of Sirte
1/10 Isis in Sirte
Isis fighters parade through in Sirte in 2015
2/10 Isis in Sirte
Islamic State (IS) group jihadists on the outskirts of Libya's western city of Sirte
3/10 Isis in Sirte
A photo of a billboard in Sirte, Libya, listing seven rules for women's clothing, saying they must be loose-fitting and undecorated
4/10 Isis in Sirte
Isis militants process down a street in the coastal city of Sirte in Libya this week; the group has heralded Libya as its ‘strategic gateway’ to attack Europe
5/10 Isis in Sirte
An Isis lecture on Sharia at the Ouagadougou complex in Sirte, Libya, in 2016.
6/10 Isis in Sirte
A sign reading "The city of Sirte, under the shadow of Sharia" as smoke rises in the background while forces aligned with Libya's new unity government advance on the eastern and southern outskirts of the Islamic State stronghold of Sirte on 9 June.
7/10 Isis in Sirte
Fighters loyal to Libya's GNA prepare to launch attacks against Isis as they continue their resistance on the outskirts of the western city of Sirte
8/10 Isis in Sirte
Forces loyal to Libya's UN-backed unity government are seen during clashes with jihadists of the Islamic State (IS) on the western outskirts of Sirte on June 2, 2016.
9/10 Isis in Sirte
Forces loyal to Libya's UN-backed unity government fire during clashes with Isis around 14 miles west of Sirte on June 2, 2016.
10/10 Isis in Libya
Isis’ Libyan branch was formed in 2014 by local militants who pledged allegiance to Abu Bakr al-Baghdadi, later being bolstered by leading Iraqi and Saudi members of the terrorist group.
The country has since been used as a training ground for Isis militants and terror attackers, with areas along its coastline including the city of Sirte temporarily taken under the group’s control in 2015.
An engineer who fled the city told The Independent how jihadis had arrived masked in a convoy of cars before seizing control and imposing the group’s bloody interpretation of Sharia law.
“They kill people and then they hang their bodies up in the streets so people can see them, as a lesson to others. The shut everything down,” Yahia bin Yahia said. “I couldn’t stay there.”
Libya has been in a state of conflict and lawlessness since Gaddafi was killed in the 2011 civil war, with the fragile new Government of National Accord struggling to exert control over swathes of the country still controlled by a plethora of warring militias.
“If the Libyans could settle their internal differences they would make quick work of Isis,” Mr Carter said.
“As long as the conditions of civil war are there, the Libyans don’t have any unity. For now, under these conditions, our help is invaluable and we are providing it.”
The defence secretary also said that Isis’ “days were numbered” in Mosul, where the US and UK are backing advancing Iraqi forces, as allies also work to “isolate” the group’s de-facto capital of Raqqa in Syria.
Libya’s conflict has also fuelled the refugee crisis, allowing thousands of migrants to be imprisoned, tortured and forced into labour or prostitution before being put on unseaworthy boats over the Mediterranean Sea.
It has also continued to destabilise northern and western Africa, allowing the free flow of weapons to rebels and extremists in countries including Mali and Sudan.