The actors demanded a stronger response by the European Union to stop the military operation that has so far killed more than 1,200 Palestinians in the Gaza Strip.
Civilians, including many children, have made up the majority of those killed in the offensive that Israel says is necessary to stop Hamas firing rockets at its cities.
The letter, printed by Europa Press and other Spanish news outlets, reads: "Gaza is living through horror these days, besieged and attacked by land, sea and air.
"Palestinians' homes are being destroyed, they are being denied water, electricity [and] free movement to their hospitals, schools and fields while the international community does nothing."
Labelling the Israeli military the "Israel Occupation Forces", it demanded an immediate ceasefire and urged Israel to "lift the blockade, which the Gaza Strip has suffered for more than a decade".
It blamed the latest hostilities on Israel’s advancement into Palestinian territories instead of observing the 1967 borders pre-dating the Six-Day War.
The letter said that Israel "humiliates, detains, and tramples on the rights of the Palestinian population in all of the West Bank every day, also causing many deaths".
Among the letter’s signatories were directors Pedro Almodovar and Benito Zambrano, actors Lola Herrera, Eduardo Noriega and Rosa Maria Sarda and two musicians, Amaral and Nacho Campillo.
Bardem, who won an Oscar in 2008 for his role in No Country for Old Men, is known for his political activism.
He previously wrote a letter published in El Diaro on the Gaza conflict, saying the attacks "only breed more hate and violence".
The actor wrote: "In the horror happening right now in Gaza there is no place for distance or neutrality… It's hard to understand and impossible to justify. And it's disgraceful that western countries are permitting such genocide."
Bardem and Cruz married in 2010 and have two children together.
The backlash to the letter has already started, with outrage among people supporting Israel’s actions on Twitter.
The Simon Wiesenthal Center, a US-based Jewish human rights group, responded with a statement saying Israel "did not start this war".
"It did what every country on this planet, including Spain, would do if hundreds of rockets were hurled at their population centres by an internationally known terrorist organisation," said founder Rabbi Marvin Hier.
Zayn Malik, Rihanna, Bill Maher and John Legend are among other celebrities to give their thoughts on the conflict in Gaza, sparking outrage on both sides.
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