Hamas called for an uprising on Monday night after violent clashes on the Gaza border resulted in a high death toll.

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"The natural reaction to the death of people who were protesting peacefully should be with an Arab and Islamic intifada (uprising)," said Khalil al-Hayya, the deputy Hamas leader. "The Palestinian response must be clear in Gaza and in the West Bank. There is no other choice but to light the fire in Gaza and in the West Bank in response to what happened."

"Hamas is monitoring the marches and stands as a shield for them," he added.

Palestinian protesters on the Gaza border (Photo: EPA)

Speaking at a border encampment, Al-Hayya said that Monday's protest was timed to coincide with the "deplorable crime of moving the US Embassy to Jerusalem."

"Our people went out today to respond to this new Zionist-American aggression, and to draw by their blood the map of their return," he said.

About 40,000 Palestinians have gathered near the fence in 13 hot spots along the border since the morning hours. Several thousand others were located in the tent area about half a kilometer from the fence. At 5:30pm, Hamas ordered all those present in the border area to return home.

Over 50 Palestinians were killed from IDF fire on the Gaza border, with over 1,200 suffering gunshot wounds and 1,200 others suffering other injuries. This is the highest Palestinian death toll since Operation Protective Edge in 2014.

The protests, which have been going on for weeks, are scheduled to culminate on Tuesday, the day Palestinians mourn as the "Nakba" or "Catastrophe" when, in 1948, hundreds of thousands of them were driven out of their homes or fled the fighting around Israel's creation.

Prime Minister Benjamin Netanyahu, who held security consultations on Monday evening in light of the clashes on the Gaza border, said Israel was acting in self-defense.

"Every country has an obligation to defend its borders," Netanyahu wrote on Twitter. "The Hamas terrorist organization declares it intends to destroy Israel and sends thousands to breach the border fence in order to achieve this goal. We will continue to act with determination to protect our sovereignty and citizens."

Hamas denied instigating the violence, but the White House backed Netanyahu. "The responsibility for these tragic deaths rests squarely with Hamas. Hamas is intentionally and cynically provoking this response," White House spokesman Raj Shah told reporters.

The IDF said in a statement: "Rioters hurled firebombs and explosive devices at the security fence and Israeli troops." The soldiers' response, it said, was in accordance with "standard operating procedures."

Defense Minister Avigdor Lieberman also held consultations on Monday evening with IDF Chief of Staff Gadi Eisenkot, instructing him "to continue acting with determination to prevent any attempt to undermine Israeli sovereignty and Israeli citizens, in accordance with the policy outlined."

The dead included at least six people under 18 years of age, including one girl. The total number of fatalities since a series of protests has now surpassed 100.

"These war crimes should not go unpunished and the international community has a responsibility to provide international protection for the Palestinian people," senior Palestinian official Saeb Erekat said after a meeting of the Palestinian leadership in the West Bank town of Ramallah.

Palestinian President Mahmoud Abbas, meanwhile, called the new US embassy, which was opened in Jerusalem on Monday, "a US settlement outpost," saying the Palestinians would reject any American mediation in peace talks with Israel and demand at least two different international mediators.

"We received Trump's peace plan; the Americans removed the issue of refugees and Jerusalem from the negotiations. We won't accept this deal and we don't want to hear from the United States anymore," he said.