The juvenile suspect remained at large and the gun was not immediately recovered following the shooting at East High School at about 10 a.m., the Denver Police Department said.
One of the administrators was critically injured and the second was in stable condition, Police Chief Ron Thomas said.
The victims were taken to area hospitals.
East High School, not far from downtown near a busy street that cuts through the city, was placed on lock-down as police investigated the shooting.
It was unclear if the shooting happened inside or outside the school. Denver Public School confirmed the victims were administrators.
Earlier this month students from the school skipped class and and marched to Colorado’s state Capitol to demand stricter gun laws, following the death of a fellow student who was shot while sitting in a car near school.