Witnesses say the al-Rawda mosque in the town of Bir al-Abed, near al-Arish, was targeted during Friday prayers.
It is the deadliest attack of its kind since an Islamist insurgency in the peninsula was stepped up in 2013.
Egyptian President Abdul Fattah al-Sisi has held emergency talks with security officials to decide how to respond.
Local police said gunmen arrived in four off-road vehicles before opening fire on worshippers,
Pictures from the scene show rows of bloodied victims inside the mosque. At least 130 people were wounded, reports say.