In a statement early on Tuesday, Judeh Murqos said: "I confirm to you that I have resigned from the government due to the violence that has occurred [on Monday] in the Gaza Strip.
"I shall give other reasons tomorrow."
Murqos, who comes from Bethlehem, was the only Christian member of the government set up by the Hamas movement after it won elections in January.
He is also the first member of Ismail Haniya's government to resign.
Palestinian factional rivalry erupted into unprecedented violence on Monday as followers of Mahmoud Abbas, the president, set fire to the parliament and cabinet offices in the West Bank while supporters of the Hamas government tried to storm a security compound in Gaza.