"I make an urgent appeal to all those conducting military operations in Syria to do everything in their power to protect civilians and civilian infrastructure, as fighting continues in Raqa and elsewhere," Guterres said in a statement.
The UN chief said he was "deeply alarmed" by the human suffering across Syria but that civilians in Raqa faced a particularly desperate situation.
"I am particularly concerned about the perilous situation for civilians in Raqa who are trapped and face threats from every direction," he said.
Tensions are runnning high between US forces and the Syrian regime in Syria, where the US-led coalition is supporting an alliance of Kurdish and Arab fighters battling to oust IS from Raqa.
The Kurdish-Arab Syrian Democratic Forces (SDF) now control four neighborhoods in the city, and on Tuesday also advanced along its southern outskirts, moving closer to completely encircling Raqa.
The UN Commission of Inquiry on Syria has expressed alarm over the "staggering" number of civilian deaths in the US- backed battle to seize Raqa.
Russia, a key ally of the Syrian government, accused the US-led coalition of "complicity with terrorism" after the drone was downed early Tuesday.
Guterres said the recent downings were "very dangerous" and could lead to an escalation of the six-year war that has killed over 320,000 people.
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