At least several people were killed in the shooting, according to a law enforcement official. Santa Fe ISD officials said in a statement that students are being taken to the Alamo Gym at 13306 Highway 6 where they will be reunited with their parents.
The Santa Fe Independent School District said "an incident occurred at the high school involving an active shooter".
Santa Fe PD and Galveston County Sheriff's department are both on the scene.
The school said there have been "confirmed injuries" but did not elaborate on numbers.
Kara, a student at the school said of the person who pulled the fire alarm, "Thank you for making a smart decision to save your classmates".
Details about whether anyone was in custody or what led to the shooting weren't immediately available.
One student told Houston television station KTRK in a telephone interview that a gunman came into her first-period art class and started shooting.
Angelica Martinez, a 14-year-old student, told CNN she and her schoolmates were being evacuated at one point "like it's a fire drill". So I told her, I said, 'Run baby, run and hide.' I said, 'Get out of there.'.
Authorities have not yet confirmed that report.
She said she couldn't describe the shooter. Aerial footage from the scene showed students standing in a grassy field and three life-flight helicopters landing at the school.
There was a large law enforcement response to the same school in February when it was placed on lockdown after students and teachers said they heard "popping sounds".
Local and federal law enforcement from around the Houston area, including agents with the Bureau of Alcohol, Tobacco, Firearms and Explosives, were responding the incident.
Santa Fe is a city of about 13,000 people roughly 30 miles southeast of Houston and 20 miles northwest of Galveston.
"We're now in protect mode as a precaution because of reports of a shooting at Santa Fe HS".