"At least 15 people were killed and 12 others injured in the Armenian district, which is home to mostly Christians and Alawites," said Rami Abdel Rahman, director of the Syrian Observatory for Human Rights.
Syria's President Bashar al-Assad comes from the Alawite community, a religious minority that stems from Shiite Islam.
Syria's state news agency SANA reported a "terrorist attack" on the main street of the district, "which caused deaths, injuries and damage."
The neighbourhood, in the east of Homs, is under government control.
Part of its Old City under rebel control has been subjected to a tight government siege that has left several thousand civilians trapped.
In recent weeks, UN and Red Crescent teams were able to evacuate some civilians and distribute food and medicine to those remaining in the besieged neighbourhoods, but the operations have halted.