AFP could not independently verify the toll which, if confirmed, would appear to be one of the largest from a single strike during 10 months of war between Israel and Hamas Palestinian militants.
Hamas denounced the "dangerous escalation" in north Gaza, which came after international mediators invited the warring sides to resume next Thursday talks towards a long-sought ceasefire and hostage-release deal.
Jordan's foreign ministry said the timing was an indication of Israel's efforts to "obstruct and thwart" the peace push.
One of the mediators, Qatar, called for an "urgent international investigation" into strikes on school shelters.
Civil defence rescuers in the Hamas-ruled territory said three Israeli missiles hit Al-Tabieen religious school in Gaza City while people performed dawn prayers.
"Their bodies were torn apart," civil defence spokesman Mahmud Bassal told AFP. "It reminds us of the first days of the war in the Gaza Strip."
With nearly all of Gaza's 2.4 million people displaced during the war started by Hamas's October 7 attack on southern Israel, many have sought refuge in school buildings, which have been hit at least 14 times since July 6, according to an AFP tally.
"Those who were inside the mosque were all killed. Even the floor above, where women and children were sleeping, was completely burned," local resident Abu Wassim said.
Israel's military said it took "numerous steps" to mitigate risks as it "precisely struck Hamas terrorists operating within a Hamas command and control centre embedded in the Al-Tabieen school".
The military has repeatedly made similar accusations after strikes on school shelters. Hamas has previously denied using schools, hospitals and other civilian facilities for military aims.
- Bodies and blood -
The attack left dead and wounded strewn around the ground floor of the two-storey complex with a courtyard, where debris lay inside and out, AFPTV images showed.
The upper floor was partially blown out and charred.
Images showed white-shrouded bodies, blood stains on the ground, and smoke rising from the rubble.
Hamas's October 7 attack resulted in the deaths of 1,198 people, mostly civilians, according to an AFP tally based on Israeli official figures.
Palestinian militants seized 251 hostages, 111 of whom are still held in Gaza, including 39 the Israeli military says are dead.
Israel's retaliatory military campaign in Gaza has killed at least 39,790 people, according to Gaza's health ministry, which does not give details of civilian and militant deaths.
Bassal told a press conference that 11 children and six women were among those killed at the school shelter, "and there are many unidentified body parts."
Israeli military spokesperson Lieutenant-Colonel Nadav Shoshani said on social media platform X that intelligence indicated "approximately 20 Hamas and Islamic Jihad militants, including senior commanders, were operating from the compound."
Saudi Arabia's foreign ministry expressed "condemnation in the strongest terms" and stressed "the need to stop the mass massacres" in Gaza.
Francesca Albanese, the United Nations special rapporteur on the rights situation in Palestinian territories, again accused Israel of "genociding" Palestinians.
Israel previously denounced her as presenting an "obscene inversion of reality".
The European Union's top diplomat Josep Borrell said the school strike left him "horrified", adding that there is "no justification for these massacres."
Turkey decried a "new crime against humanity" and claimed Israeli Prime Minister Benjamin Netanyahu wanted "to sabotage ceasefire negotiations".
- Rare intervention -
Iran this week accused Israel of wanting to spread war in the Middle East, while Hamas officials, some analysts and critics in Israel have said Netanyahu seeks to prolong the fighting.
However, Netanyahu's office on Thursday said Israel would send negotiators "to conclude the details of implementing a deal", after the joint invitation from the United States, Egypt and Qatar.
They invited the warring parties to resume talks on August 15 to swiftly implement an agreement, after intense diplomacy aimed at averting a region-wide conflagration.
The Gaza war has already drawn in Iran-aligned groups around the region.
Fears of a broader Middle East war have surged following vows of vengeance from Lebanon's Hezbollah movement, Hamas, Iran and others for the killing of two senior militants, including Hamas's political leader.
In a rare intervention on Saturday, Iraq's top Shiite Muslim cleric, Grand Ayatollah Ali Sistani, denounced "crimes" including the latest school strike and the senior militants' killings which, he said, risk "catastrophic consequences".
The killing on July 31 of Hamas's Ismail Haniyeh during a visit to Tehran had sidelined truce talks. Iran and Hamas blamed Israel, which has not directly commented.
Iran's mission to the United Nations on Saturday said the Islamic republic has "the legitimate right to self-defence" after its sovereignty was "violated".
"However, we hope that our response will be timed and conducted in a manner not to the detriment of the potential ceasefire," it said.
Haniyeh's death came hours after an Israeli strike on south Beirut killed Fuad Shukr, Hezbollah's military chief. Israel said this was in response to rocket fire that killed young people in the annexed Golan Heights.
Hamas ally Hezbollah has been trading near-daily cross-border fire with Israeli forces.
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