The four handed in their letters of resignation together to Prime Minister Hisham Qandil, a senior government official said.
Tourism minister Hisham Zazou had already tried to resign last month after Morsi appointed Adel al-Khayat, a member of an Islamist party in Luxor, as governor of the temple city.
Morsi on June 16 named Khayat along with 16 other new governors, including seven from his Muslim Brotherhood movement.
Monday's resignations come amid a campaign of civil disobedience and a day after massive nationwide protests against Morsi and his Muslim Brotherhood.