"A full-scale invasion on Rafah would be a humanitarian catastrophe. We appeal to Israel not to proceed,” Tedros said on X.
"We urge all parties to work for a ceasefire and lasting peace.”
His remarks came after Israeli Prime Minister Benjamin Netanyahu vowed Tuesday to invade Rafah, despite reports of a possible cease-fire deal with Hamas.
Netanyahu said the Israeli army would enter Rafah to destroy Hamas’ battalions there "with or without a deal."
His statements came amid reports of a new cease-fire proposal being discussed by Hamas and Israel to end the conflict in Gaza.
Israel has waged an unrelenting offensive on Gaza since a cross-border attack by the Palestinian group Hamas last Oct. 7 which killed some 1,200 people.
More than 34,500 Palestinians have since been killed, mostly women and children, and thousands of others injured amid mass destruction and severe shortages of necessities.
More than six months into the Israeli war, vast swathes of Gaza lay in ruins, pushing 85% of the enclave’s population into internal displacement amid a crippling blockade of food, clean water and medicine, according to the UN.
Israel stands accused of genocide at the International Court of Justice. An interim ruling in January ordered Tel Aviv to stop genocidal acts and take measures to guarantee that humanitarian assistance is provided to civilians in Gaza.