Many of the victims are thought to be women and children.
Egypt's Christian minority has often been targeted by Islamist militants. Christians gathered to show anger at the attack, the worst in years, BBC writes.
Egypt has seen a wave of attacks by militants since 2013 when the military overthrew President Mohammed Morsi, an elected leader who hailed from the Muslim Brotherhood, and launched a crackdown against Islamists.
Some of Mr Morsi's supporters blamed Christians for supporting the overthrow.
Video footage showed the interior of the church littered with broken and scattered furniture, along with blood and clothing on the floor.
"I found bodies, many of them women, lying on the pews (kirkebænkene). It was a horrible scene," said cathedral worker Attiya Mahrous, according to the BBC.
President Abdul Fattah al-Sisi has declared a three-day period of national mourning. He called for the perpetrators to be hunted down.
Coptic Christians make up about 10 per cent of Egypt's population. St Mark's Cathedral is the headquarters of the Coptic Orthodox church, and the home of its leader, Pope Tawadros II.
The Church separated from other Christian denominations at the Council of Chalcedon (451 AD) in a dispute over the human and divine nature of Jesus Christ.
Egypt's Coptic Christian minority has long complained of discrimination. In February this year, a court sentenced three Christian teenagers to five years in prison for insulting Islam. The teenagers had appeared in a video, apparently mocking Muslim prayers, but claimed they had been mocking the Islamic State (IS) group following a number of beheadings.
