Dozens of international aid groups face de-registration by December 31, which then means they have to close operations within 60 days, said the UN and more than 200 local and international aid groups in a joint statement.
"The deregistration of INGOs (international aid groups) in Gaza will have a catastrophic impact on access to essential and basic services," the statement read.
"INGOs run or support the majority of field hospitals, primary healthcare centres, emergency shelter responses, water and sanitation services, nutrition stabilisation centers for children with acute malnutrition, and critical mine action activities," it said.
While some international aid groups have been registered under the system that was introduced in March, "the ongoing re-registration process and other arbitrary hindrances to humanitarian operations have left millions of dollars' worth of essential supplies - including food, medical items, hygiene materials, and shelter assistance - stuck outside of Gaza and unable to reach people in need," the statement read.
Israel's mission to the United Nations in New York did not immediately respond to a request for comment on the statement.
Under the first phase of US President Donald Trump's Gaza plan, a fragile ceasefire in the two-year-old war between Israel and Palestinian militants Hamas began on October 10. Hamas released hostages, Israel freed detained Palestinians and more aid began flowing into the enclave where a global hunger monitor said in August famine had taken hold.
However, Hamas says fewer aid trucks are entering Gaza than was agreed. Aid agencies say there is far less aid than required, and that Israel is blocking many necessary items from coming in. Israel denies that and says it is abiding by its obligations under the truce.
"The UN will not be able to compensate for the collapse of INGOs' operations if they are de-registered, and the humanitarian response cannot be replaced by alternative actors operating outside established humanitarian principles," the statement by the UN and aid groups said.
The statement stressed "humanitarian access is not optional, conditional or political," adding: "Lifesaving assistance must be allowed to reach Palestinians without further delay."
