Manuel A. Roxas High School embarked on its beginning from the womb of Manila South High School that was later renamed Araullo High School in honor of the third Chief Justice of the Philippines, Manuel Araullo. To meet the increasing number of enrollment, Araullo High School created Annexes and much later the Canonigo Annex.

In 1921, the Manila city government established a secondary school in each of its four districts: Manila North High School, Manila West High School, Manila East High School, and Manila South High School.

The location of Manila High School was directly located at the south of the mouth of Pasig River and was renamed Manila South High School. Later on, in June 1930, it was then again was renamed Araullo High School in memory of Justice Manuel Araullo. The three other schools were named after jurists; Florentino Torres (Manila North) High School in Tondo, Cayetano Arellano (Manila West) High School, and Victorino Mapa (Manila East) High School.

The bombing of Intramuros during World War II destroyed the Araullo High School. It reopened in 1946 in Quonset huts in Singalong where it opened classes in the compound of Lukban Elementary School. When the Singalong site was occupied by the Epifanio de los Santos Elementary School, Araullo High School then moved to the Border Building on Padre Faura.

In November 1947, the Division of City School acquired two Quonset Huts in Mehan Garden, formerly occupied by Surplus Property Commission, Mr. Victor Hernandez was chosen to organize the annex to accommodate the increasing number in enrollment of all public secondary schools in the city. The classes opened on December 15, 1947, with an initial enrollment of 221 first-year students.

Historically, Manuel A. Roxas High School (MARHS) was the first school named after the fifth President of the Philippines, and the first school established after the war, and the first addition to the old schools organized before it. Born out of five Quonset huts acquired from the Surplus Property Commission, Manuel A. Roxas High School slowly but steadily expanded to accommodate increasing enrollment.

From 503 students in 1948 when it became independent to 6,710 in 1957, the need for a bigger place to accommodate the steadily increasing enrollment pressed the city council to acquire the 13, 000 square meter lot in Canonigo Street, near the Paco Railway Station. Initiated by Councilor Gonzalvo Santos Rivera, the City approved the sale on October 9, 1958, and the area was cleared of squatters. Thereafter, a thirty-standard-room L-shaped building began to rise with Ms. Arsenia de Jesus as principal. Manuel A. Roxas High School grew in size and beauty with the continuing number of newly constructed buildings.

Following the 1990 earthquake that hit Manila, the four-story Roxas High School building with a roof deck was declared condemned in 2006. A four-story 220-million-peso main building replaced the L-shaped main building.