It is believed that the site of this mosque was once occupied by Ptolemy II Philadelphus, and is where a group of Jewish scholars translated the Torah from Hebrew into Greek. In about 282–300 CE, the Church of Saint Athanasius was erected on this site by Pope Theonas and later transformed into the larger Church of the Virgin Mary. By the sixth century the church was in ruins and it was replaced by the Mosque of One Thousand Columns during the Arab conquest of Egypt. This mosque, also known as the Western Mosque, was built by Amr Ibn El Aas.
Centuries later, at the time of the French Expedition, Gratien le Père observed that this mosque had no longer been used for prayers in ages, while Saint-Genis also noted that many of the mosque’s elements were reused to construct other buildings. During the French Campaign of Egypt, the mosque was employed by the French army as a depot for arms and ammunition.
Then, Mohamed Ali transformed the remnants of the mosque into an army hospital for the Egyptian navy and ground troops. Under the reign of Khedive Ismail, in around 1872, the building was utilized as a police camp. In 1884, under Khedive Tewfik, the land on which the mosque stood was divided up. A part was sold to the Karam brothers to serve as a wood depot, which it has remained to this day. Another part was used to build the Convent of Saint Francis of Assisi in 1881, which was destroyed during World War I, rebuilt in 1925, and renamed the Church of Santa Rita in 1969 as testified by the plaque near one of the church entrances. In the twentieth century, a state school was built in place of the few remnants of the mosque. Today, nothing remains of the Mosque of One Thousand Columns.