Ramon Magsaysay, the 7th President of the Philippines, was the first to envision a Science High School in the Philippines in his 1956 State of the Nation Address where he underscored the great need of stepping up the development of fundamental and applied research in science and technology which has "long been neglected.

With 36 students screened through a competitive examination, this nucleus of a science high school had its beginnings in a single-story building in Intramuros.

After five years in Intramuros, the school moved to its present site in Ermita in 1966 with its first principal, Honesto Valdez (1963–1977).

In September 1977, Evelina P. Barotilla, the second principal, saw the completion of the Manila Science High School Complex and the renovation of the H.A.

The whole construction project was financed by the Special Education Fund under the chairmanship of Dr. Josefina Navarro, Superintendent of City Schools, Manila.

[5] From that year until 2000, Manila Science High School was further sharpened under the supervision of Daisy H. Banta.

The new millennium ushered in the arrival of Susan A. Yano, the fourth principal, the completion of the Antonio Maceda Building, and the revival of the Manila Science High School Alumni Association.

[6] During the tenure of principal Flora A. Valdez, a government project in the Amadome was completed in time for the new school year, being formally inaugurated and turned over by Manila 5th District Representative Amado Bagatsing, the project's namesake, on September 8, 2010.

A groundbreaking ceremony for the construction of a new 10-storey building with a roof deck was held on July 26, 2021, during the mayorship of Isko Moreno.

[8] On December 14, 2023, the new building was inaugurated and was turned-over to the school administration by Mayor Honey Lacuna.

JHS students take multiple science and mathematics courses per year in contrast with the Department of Education's prescribed curriculum for regular schools.

In addition, information technology and computer science subjects are offered for all JHS grade levels.

By the succeeding years they will take separate courses, each with full focus on one branch or subbranch of science.

Core subjects for all JHS students focus on algebra, statistics, geometry, trigonometry, and precalculus.

Albeit, the competencies and teaching standards for these core courses were raised to keep up with the academic aptitude of the students.

Elective courses offered include specialized topics in STEM, as well as journalism, business management, foreign languages, and technical writing.

School organizations are responsible for holding co-curricular and extracurricular activities, ensuring that students are not overly preoccupied with academic matters.

Students are organized into class sections, a standard system adopted for all basic education institutions in the Philippines.