Security will be extremely tight with Egypt under a state of emergency following two bombings in Coptic churches earlier this month.
The 80-year-old pontiff is due in Cairo around 1400 (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.
On Friday the head of the world's 1.3 billion Catholics will walk together with Coptic Pope Tawadros II to the church where a suicide bomb attack killed 29 people in December.
Police and soldiers stood guard outside the Vatican residence in Cairo on Friday and armoured cars were stationed outside the Coptic Orthodox Saint Mark's Cathedral, which Francis will also visit.
All of the country's churches have been placed under additional protection because of the risk of another assault timed to coincide with Francis being in the country.
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 golf carts.
"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.
Before his visit, some roads had been festooned with posters showing Francis against the backdrop of the Pyramids, with a message that read: "Pope of peace in the Egypt of peace."
Francis will meet privately with the grand imam, Sheikh Ahmed al-Tayeb, an Islamic philosophy professor who visited the Vatican last year and is considered one of the leading authorities in Sunni Islam.
Francis is then due to give a speech in an international conference for peace organised by Al-Azhar, a seat of learning for 1,000 years as well as a celebrated mosque.
John Paul II was the last pope to have visited Egypt in 2000, with his arrival also coming weeks after anti-Christian violence that killed about 20 Copts in January that year.
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 now-retired German pontiff's 2011 comments condemning an attack on a Coptic church prompted Al-Azhar to denounce Benedict for meddling in Egypt's affairs.
Francis will also meet Friday with Tawadros II at his seat in Saint Mark's Cathedral before visiting the nearby Coptic church of Saint Peter and Saint Paul, the target of the December bombing claimed by IS.
The attack was the deadliest targeting the Coptic community since the 2011 suicide bombing that killed 23 people in Alexandria.
The pope will be joined at the international conference by Ecumenical Patriarch Bartholomew, Archbishop of Constantinople, the spiritual leader of the Orthodox world and a close ally.
The Argentine will also meet with President Abdel Fattah al-Sisi, who has been criticised internationally for human rights abuses but is seen as something of a friend to Egypt's Christian minority.
In 2015, he became Egypt's 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 percent of the country's population of 92 million, are the Middle East's largest Christian minority and one of the oldest.
But they have suffered attacks throughout the years and many complain that they feel like second-class citizens.