He told Parliament that the attack was legally justified because the militants were plotting lethal attacks against Britain and the fighters could not be eliminated any other way.
"There was a terrorist directing murder on our streets and no other means to stop them," Cameron said, adding that the decision to launch the attack hadn't been taken lightly.
The prime minister said the deadly Royal Air Force strike was permissible because of Britain's intrinsic right to self-defense and had been approved by the attorney general.
The Aug. 21 attack on a car in the Syrian city of Raqqa, an IS stronghold, represents an escalation for Britain, which had not participated in military actions in Syria. Cameron said the threat made action mandatory.
Cameron said that after "meticulous planning" British nationals Reyaad Khan and Ruhul Amin were killed along with another IS militant who was not identified.
He said Britain took action after determining that Khan and another Briton identified as Junaid Hussain were "British nationals based in Syria who were involved in actively recruiting Isil (IS) sympathizers and seeking to orchestrate specific and barbaric attacks against the West, including directing a number of planned terrorist attacks right here in Britain, such as plots to attack high profile public commemorations, including those taking place this summer."
He said it was their intention to murder British citizens. There was no information indicating that Hussain, the other British national cited by the prime minister as planning attacks, had been injured or killed.
The prime minister said the threat from Islamic State fighters was more acute than ever before and that the drone attack was the only "feasible means" of dealing with the danger in this case.
No civilians were killed in the strike, which was carried out independent of coalition military activity taking place in the region, he said.
Parliament was not consulted in advance. Cameron said the government reserves the right to take future action without prior approval when there is a "critical" British interest at stake or when a "humanitarian catastrophe" is imminent and can be averted.