"Earlier this morning, a WFP plane dropped the first cargo of 21 tonnes of items into Deir Ezzor," in eastern Syria, UN aid chief Stephen O'Brien said.
Reports from aid teams on the ground confirm that "pallets have landed in the target area as planned", he told a UN Security Council called to discuss the humanitarian crisis.
UN agencies are working to scale up aid deliveries to Syria before a cessation of hostilities enters into force at midnight Friday to shore up peace efforts.
Last month, Russia said it had dropped aid into Deir Ezzor, where some 200,000 people are in dire need of food and medicine since IS fighters surrounded the city about a year ago.
The air drops carried out by the World Food Programme are considered less efficient than land deliveries, but O'Brien argued that there were "benefits to this approach as a last resort."
The UN aid chief said some 110,000 people living in besieged towns had received aid and that deliveries to a further 230,000 people in cut-off areas including through air drops had been approved.
"We are still waiting for approval for an additional 170,000 people. We expect those approvals to happen immediately," he said.
- Syria 'doing its best' -
Signup to our newsletter and follow us on Facebook and Twitter!
Syrian Ambassador Bashar Jaafari accused the United Nations of using the humanitarian crisis as a political tool and argued that no such attention was directed to Yemen, which he argued was in a much worse state.
"It is clear that our government is doing its best to deliver assistance," he told the council.
The ambassador blamed armed groups for civilian suffering and said delays in approving aid deliveries were due to concerns for the safety of humanitarian workers.
"We have not witnessed any humanitarian crisis other than in the areas where these terrorist groups entered," he said.
The United Nations is calling on all sides to lift starvation sieges across Syria, where it estimates that 487,000 people live, although some non-governmental organizations say the figure is much higher.
The council has approved several resolutions demanding full access for humanitarian workers, but these have been largely ignored.
O'Brien stressed that the ceasefire deal agreed by the United States and Russia must produce an "immediate end" to attacks on civilians and civilian infrastructure such as hospitals, schools and markets.
"Enough is enough. This brutality must be brought to an end," he said.
More than 260,000 people have died in Syria's conflict, which began in March 2011 with anti-government protests but has since imploded into a multi-sided proxy war.