The cause of the blaze was not immediately known, nor was the number of children among those killed.
Commanders have "informed us that they have already counted 19 people deceased" in the Virgin of the Assumption Safe Home located in San Jose Pinula, a village just to the east of the capital, the fire services spokesman, Mario Cruz, told reporters.
Another 25 people were injured, suffering burns of various degrees. They were taken to state hospitals in Guatemala City.
Initial reports suggested that some of the children and teenagers in the shelter had protested overnight against poor food and treatment by staff.
It has been the target of multiple complaints alleging abuse, and several children have run away.
The country office of the UN children's fund UNICEF said on its Twitter feed it "condemns the tragedy" and emphasized: "These children and adolescents must be protected.