Police say two people were killed in a direct strike on a vehicle in the city of Lod.
One woman in her 40s was declared dead at the scene and a second person died after being taken to hospital. Hebrew media reports said she was a 7-year-old girl.
A third person was seriously wounded in the direct hit.
Police called on people to remain near bomb shelters.
The city, a mixed Arab-Jewish city, was the scene of violent riots earlier in the evening.
Lod Mayor Yair Revivo said the dead were from the Arab community.
“Hamas missiles do not differentiate between Jews and Arabs,” Revivo said.
He also appealed to Arab residents to end the protests and calls for calm in the city. “The day after we will still have to live here together.”