The 80-year-old pontiff is due in Cairo around 14.00 local time (1200 GMT) and his 27 hours on Egyptian soil will include a meeting with the grand imam of the Al-Azhar mosque, sealing a recent improvement in relations between Catholicism and the Sunni branch of Islam.
Security will be extremely tight with Egypt under a state of emergency following two bombings in Coptic churches earlier this month that killed 45 people.
The most recent attacks have been claimed by the Islamic State (IS) group whose propagandists regularly boast of their intention of mounting attacks on the Vatican, as well as Egypt's Coptic Christians.
Despite the dangers, Francis is expected to conduct most of his business in a normal vehicle and electric pope mobile- style golf carts.
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"Please pray for my journey tomorrow as a pilgrim of peace to Egypt," Francis said on his Twitter account on the eve of his departure.
He is then due to give a speech as a "simple participant" in an international conference for peace organised by Al- Azhar, a seat of learning for 1,000 years as well as a celebrated mosque.
Vatican dialogue with the Muslim world, a priority for this pope, was set back significantly when Francis's predecessor Benedict XVI made a speech in 2006 in which he was seen as linking Islam to violence.
The head of world's 1.3 billion Catholics will also meet Friday with the Coptic Pope Tawadros II.
The two men are due to walk together to the Coptic church of Saint Peter and Saint Paul in the heart of Cairo, which was hit by a bomb attack in December claimed by IS that killed 29 people.
The attack was the deadliest targeting the Coptic community since the 2011 suicide bombing that killed 23 people in Alexandria.
The Argentine will also meet with the country's strongman President Abdel Fattah al-Sisi, who has been criticised internationally for human rights abuses but is seen as something of a friend of Egypt's Christian minority.
In 2015, he became the first head of state to attend a Christmas mass.
On Saturday, the pontiff will preside over a mass for the country's small Catholic community, estimated to number around 272,000 spread across various rites.
Egypt's Copts, who make up about 10 per cent of the country's population of 92 million, are the Middle East's largest Christian minority and one of the oldest.