Midwood High School was opened on February 3, 1941 to 2,600 students. The school was built for a cost of $2,175,000.   Adjusted for inflation, that would be roughly $33,519,413 in 2011 dollars. The school structure was designed by architect Eric Kebbon with neo-classical and neo-Georgian elements, including a Georgian cupola and Ionic columns.

Several things were located on the site before the school was built.  The land was originally all part of the 95-acre Ditmas-Van Brunt farmstead. The Ditmas Homestead was located on Campus Road and East 27th Street. The Flatbush Avenue Trolley ran straight through the farm. On one side of Bedford Avenue, P.S.152 was built in 1906. The Wood Harmon Corporation bought the land where both Midwood and Brooklyn College are located now. In 1908, they built the Flatbush Golf Course on the land. In 1931 the course was closed and for several years the land was used by the Barnum and Bailey Circus. In 1915 the Kenilworth Church was built.  It occupied the site until 1937, when it was condemned and relocated several blocks away.

In 1935, New York City purchased 42 acres of land at the site.  In 1939 they broke ground for Midwood High School across from the recently opened Brooklyn College campus. Although the school opened its doors to students on February 3, 1941, the dedication was not held until May 8, 1941.  It was attended by several luminaries, including Mayor Fiorello LaGuardia.