Israel's attack on the Nasser hospital in south Gaza, in which at least 20 people were killed including five journalists, was "completely unacceptable", the EU Commission said.
"Civilians and journalists must be protected under international law," Commission spokesperson Anouar El Anouni said at a press briefing.
"Civilians in Gaza have been suffering for far too long and far too much, and it is time to break the cycle of violence."
An unprecedented number of former EU and national ambassadors, as well as former senior EU officials, have signed a fresh letter urging the EU to take tougher action against Israel over the worsening humanitarian situation in Gaza.
The joint letter has been signed by 206 former European ambassadors and officials.
That compares to a previous letter sent in July, which had 58 signatures.
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The joint letter reflects deepening anger at Israel's actions in Gaza and the EU's inability to forge a tougher, more unified response.
It is understood that the official UN confirmation of famine conditions in Gaza at the weekend added a sense of urgency to the letter.
The signatories include 74 former ambassadors representing the EU overseas, and 96 former national ambassadors from Germany, France and Italy.
Former senior officials from EU institutions have also signed the letter, including 24 directors general of EU institutions.
Ten Irish diplomats who served as EU ambassadors overseas, including former tánaiste Eamon Gilmore, have added their names to the letter, as have a former director general from the European Commission, and a former director of the EU council secretariat.
The letter has been addressed to European Commission President Ursula von der Leyen, European Council President António Costa and European Parliament President Roberta Metsola.
It has also been sent to EU foreign policy chief Kaja Kallas, a number of other relevant EU commissioners, and to the leaders and foreign ministers of the 27 EU member states.
The earlier letter, sent on 23 July, followed the blocking by a number of pro-Israel member states, of a string of potential EU sanctions against Israel over its conduct in Gaza.
Following a meeting of EU foreign ministers on 15 July, Ms Kallas said ten possible sanction measures against Israel had been paused after an agreement reached with Tel Aviv to increase the flow of aid into Gaza.
However, the updated letter states: "We note with dismay that, in the ensuing four weeks since our (last) letter, no ceasefire has been agreed in Gaza, no Israeli hostages have been released, and, alarmingly, the Israeli government has begun implementing plans to empty Gaza City and its environs of one million Palestinians, by forcing them into concentration areas in the south, in preparation for possible large-scale deportations to third countries with the risk of fomenting a migration crisis.
"If this was not bad enough, the Integrated Food Security Phase Classification (IPC) confirmed on 22 August that a man-made famine now exists in these same areas of Gaza, with half a million people there facing starvation, destitution and death.
"Malnutrition now threatens the lives of 132,000 children under five through June 2026, and by the end of September 2025, it is estimated that 640,000 people (a third of the population) will face catastrophic levels of food insecurity.
"Tragically, already over 200 Gazan citizens, including over 60 children, have succumbed to malnutrition-related deaths."
The letter said that more than 2,600 Palestinians had been killed in Gaza since the July letter, many of them women and children, and it condemns Israel’s continued prevention of the UN agency, UNRWA, from providing humanitarian aid.
It further denounces the Israeli government’s plans to expand illegal settlements in East Jerusalem through the construction of 3,400 housing units, which, the authors state, is part of an "openly declared aim … to sabotage the longstanding two-state solution, backed by the vast majority of UN member states and the EU".
The former ambassadors and officials add: "We express our profound disappointment that, in response to the deteriorating situation in Gaza, no substantive measures have been taken by the EU to pressure Israel to end its brutal war, to resume vital humanitarian assistance by mainstream providers, and to dismantle its illegal occupation of both Gaza and the West Bank.
"We underline that, if the EU fails to take an effective stand, only member states individually or in 'groups of like-minded countries' will act. While this is welcome in itself, it will not have the full force of EU-wide collective action."
Dr Michael Doyle, an Irish former EU official involved in managing EU responses to international crises for two decades, and who served as EU ambassador to Lesotho from 2014-2017, was a member of the European team coordinating the letter.
He told RTÉ News: "There has never been anything like this done before by former EU ambassadors or senior officials. Having worked for decades as officials in Brussels and as EU ambassadors promoting our European values based policies around the world, it was not an easy decision for any of us to take on this initiative.
"However, the dire situation being endured by Palestinians in Gaza, and also the West Bank, has required us to come together and speak out to strongly urge the European Union and its member states to urgently take effective and substantive actions in the context of multiple daily violations of International Humanitarian Law."
He said the group aimed to achieve maximum impact on European political leaders and their decision making by providing "focused and timely" public commentary on the conflict, whilst urging member state governments and the EU institutions to take effective action towards both ending the war in Gaza and Israel's occupation of Gaza and the West Bank, and to promote a sustainable two-state solution.
He said one aim of the latest letter is to alert EU member states as to the concrete and impactful actions they could take individually or in groups of like-minded countries in the absence of unified EU action, which until now is being blocked by certain member states.
The Tánaiste has said that collective EU action is "long overdue", adding that there are "clear, concrete measures the EU can take".
Describing the letter as a "vital, unprecedented intervention", Simon Harris said: "If we don't take collective action now against the backdrop of famine, when will we?
"Collective EU action could make a powerful difference."
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Writing on X, he said: "In the absence of collective action, groups of members states should seek to work together but this would not be as impactful or effective and be a indictment on our ability to act as a collective at a time when the EU itself has found Israel in breach of the Association Agreement.
"EU Foreign Ministers meet in Copenhagen this week and I look forward to discussing this directly with counterparts."
The former director of aid agency UNWRA Richard Wright has called on the entire European Union to collectively recognise a Palestinian state.
Mr Wright, who is a former EU ambassador to Moscow, said those who signed the letter all "dedicated their lives to the European Union, its values and principles for the people and for the world".
"If we are going to be serious about what the European Union is, what it stands for, what its principles are, and a beacon of the defence of human rights and international humanitarian law for the rest of the world, the global south … we have to act," he said.
"All of us feel very strongly that action is necessary."
