With the support and determination of former Mayor Soledad C. Eusebio, Hon. Mayor Vicente P. Eusebio, and the member of the City Council, the school was founded on October 7, 2004, by virtue of City Ordinance No. 28, series 2004. It was named Pasig City Science High School.

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The school formally opened in School Year 2005-2006 using temporarily the fifth, sixth, and seventh floors of the Pamantasan ng Lungsod ng Pasig building. Mr. Noel A. Salalima became its first principal. Ms. Edna H. Negru and Ms. Mila I. Jose were appointed as the Head Teachers together with the first batch of faculty composed of nineteen (19) competent special science teachers. Four (4) support staff aided the administrators.

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In January of 2014, Chief Education Program Supervisor Mrs. Ligaya Insigne took over the school as OIC-Principal, bringing with her the mandate from the Office of the Mayor to hone the future leaders and young scientists. In June of 2014, the reign of Pasig City Science High School was under the stewardship of Mr. Jay Mathias A. Arellano.

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Currently, Pasig City Science High School continues its legacy under the strong leadership of Mr. Charlie O. Fababaer. As a homegrown school leader, our Principal endeavors to fulfill the school's mission and vision—to fully develop well-rounded, nurturing, and excellent students who are globally competitive and responsive to the ever-changing needs of the time in the field of Science and Technology.