Sistani also urged an end to the "genocidal war" in Gaza, where the civil defence agency said an Israeli air strike Saturday on a school housing displaced Palestinians killed more than 90 people.
"Once again, the Israeli occupation army has committed a huge massacre... adding to its series of ongoing crimes" in Gaza, Sistani said in a rare statement since the start of the 10-month-old war.
The recent high-profile killings of two leaders of Hamas and Hezbollah increased the danger of "major clashes" that could have "catastrophic consequences" for the region, he warned.
"We once again call on the world to stand against this terrible brutality," Sistani said, urging Muslims "to unite in order to press for an end to the genocidal war" in Gaza.
On July 31, Palestinian militant group Hamas's political leader Ismail Haniyeh was killed in an attack, blamed on Israel, in the Iranian capital.
It came hours after Israel killed Hezbollah senior military commander Fuad Shukr in a strike on the Lebanese group's stronghold in south Beirut.
The assassinations, which prompted vows of retaliation by Iran and Hezbollah, are among the most serious in a series of tit-for-tat attacks that has heightened fears of a regional conflagration stemming from the Gaza war.
Most of Gaza's 2.4 million people have been uprooted by the war triggered by Hamas's October 7 attack on southern Israel.
Gaza's civil defence agency said Saturday's strike on a school housing displaced Palestinians killed 93 people. Israel's military accused militants of using the building as a command centre.
AFP could not independently verify the toll which, if confirmed, would appear to be one of the largest from a single strike during the Gaza war.
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