Also known as the Hanging Church because it is seated above a 2nd Century Roman fortress, it was home to the Coptic pope until the 13th Century.
Prime Minister Ibrahim Mahlab and Coptic Pope Tawadros II attended the opening ceremony at the church.
Christians make up about 10% of Egypt's mainly Muslim population.
Many Christians were sympathetic to the overthrow of President Mohammed Morsi last year and dozens of churches were damaged in the ensuing violence.
President Abdel Fattah al-Sisi has called for Christians and Muslims to be united and is said to have a good relationship with Pope Tawadros.
Prime Minister Mahlab said the restoration, which cost more than $5m (Â£3m), was delayed by engineering challenges posed by subterranean water courses.
He was taken on a tour of the church to learn more about the renovation process.
The church is in a compound close to Cairo's first mosque and one of the oldest synagogues.
The restoration of one of Egypt's oldest Coptic Christian churches, the Virgin Mary church in Cairo, has been completed after 16 years.