The demonstrators accused Egypt's government of not doing enough to protect the Christian community and called for the resignation of Egypt's interior minister.
"This is the government's responsibility. The explosion happened inside the church," said Gebrail Ebeid, who was heading to services when the bombing took place,
"How can this happen? What did I do to have this happen as I am going into the church?" Ebeid said.
"Where were the security forces? They're filling the streets now, but it's too late."
The attack drew condemnation from political and religious leaders and led President Abdel Fattah al-Sisi to declare three days of national mourning.
Interior Minister Magdy Abdel Ghaffar rushed to the scene after the blast and Prime Minister Sherif Ismail called on security services to quickly find those responsible.
"The nation's Muslim and Christian citizens stand together against this black terrorism," Ismail said in the statement.
Sisi too condemned the attack, saying in a statement: "Egypt will only emerge stronger and more unified from these events."
Sheikh Ahmed al-Tayeb, the head of Egypt's top Sunni Muslim authority al-Azhar, said the "vile terrorist explosion" was "a great crime against all Egyptians".
The explosion struck inside a church near the seat of the Coptic pope who heads Egypt's Christian minority, at around 10:00 am [0800 GMT], security officials said.
At least 25 people were killed and 31 others wounded, according to the health ministry.
A bomb made of 12 kilos of TNT appeared to have been behind the explosion, security officials said.
The blast shattered the church's glass windows and scattered pews through the main prayer hall. Blood stains could be seen on the floors, where shoes and other belongings lay scattered.
The attack was the worst on the Coptic Christian community since a 2011 suicide bombing killed more than 20 worshippers outside a church in the coastal city of Alexandria.
There was no immediate claim of responsibility for the bombing but Coptic Christians, who make up about 10 percent of Egypt's population, have been previously targeted in militant attacks.