The emotional mass came as the Catholic pontiff visits Egypt to support the country's embattled Christian minority and promote dialogue with Muslims.
Francis and Coptic Pope Tawadros II sat near the altar of Saint Peter and Saint Paul church where an IS suicide bomber killed 29 people in December.
The two leaders - one wearing his trademark white robes and skullcap, the other in black embroidered with gold and a satin black turban - listened to hymns sung to the accompaniment of clashing cymbals.
On December 11, Coptic Christians were in mid-prayer when a devastating blast tore through the church, spraying shrapnel into worshippers and the icon-covered walls and blowing out the tiled roof.
But for the Catholic pope's visit icons lining the wall of the church have been restored and white flowers adorned the central aisle between the pews.
Some of the building's pillars still appear to bear the scars of the attack, and a transparent panel covers a section of bloodstained wall.
Pope Francis leaned over to touch the panel, a ghastly reminder of December's carnage.
Earlier, Francis and Tawadros had entered the church, closely hemmed by bodyguards.
Francis had joined a procession from the nearby headquarters of Tawadros, led by church members holding standards bearing the portrait of Jesus Christ.
After mass, the Argentine pontiff paused outside the church to pay his respects to the victims of the attack.
Tiny portraits of those killed by the IS suicide bomber were on display.
The Catholic and Coptic popes prayed in silence, hands held together and heads bowed, as clerics laid white flowers in front of the makeshift memorial.
Egypt has faced a series of jihadist attacks targeting its Christian minority, which makes up around 10 percent of the country's population of 92 million.
The December attack was followed by twin church bombings in the cities of Tanta and Alexandria earlier this month on Palm Sunday, that were also claimed by IS and killed 45 people.
Earlier today, the pontiff and Tawadros embraced at they met outside Saint Mark's Cathedral, the Coptic religious leader's headquarters.
Banners featuring both popes spilled down the building's facade, as Francis embarked on the latest step of a tightly controlled visit.
Tanks guarded the headquarters where only those with invitations were permitted to enter.
Policemen were stationed every few metres (yards) in the surrounding central Cairo middle-class neighbourhood, sometimes searching the bags of passers-by.
Members of the security forces also monitored the streets below from rooftops.
Tawadros welcomed the pope with a speech in a room adorned with illustrations of stories from the Coptic tradition.
One portrayed the Holy Family in Egypt, Mary atop a donkey and cradling the baby Jesus, Joseph by her side.
The Bible speaks only briefly of the flight to Egypt, on orders from the Archangel Gabriel after King Herod decided to kill all male newborns under his jurisdiction.
But Coptic texts speak of a lengthy three-year odyssey by the Holy Family through Egypt, punctuated by miracles.