In 1922 the Mobile County Public School System (MCPSS) began to plan for the construction of a new high school that would serve the entire county, as the facilities of Barton Academy, in downtown, were becoming overcrowded. In 1923 the Mobile County School Board acquired 38 acres (15.4 ha) from the Carlen family for the site of their proposed high school complex. The cornerstone of the school was laid on 14 December 1925, and on 26 April 1926, Mobile High School opened. Construction costs totaled $850,000 for the first six buildings with an additional $200,000 spent on the gymnasium and the indoor pool installed in 1930. Two years after its opening the school's name was changed to Murphy High School in honor of Samuel Silenus Murphy, MCPSS superintendent from 1900-1926. While still called Mobile High School, the yearbook had been called the "Mobile High Annual". At the change of the name to Murphy High School, the workers did not want to change the name of the yearbook. They agreed to shorten the name to "Mohian", or a shortened version of Mobile High Annual.
The school was desegregated in 1963 when three African American students brought a case against the Mobile County School Board for being denied admission to the then all-white school. The court ordered that the three students be admitted to Murphy for the 1964 school year. By the Fall of 1970, following stringent desegregation efforts within Alabama, 1,500 of the school's 2,140 students were African American. At the same time, the school had 34 African American teachers on its 87-member faculty.
On December 25, 2012, Murphy High School was hit directly by a strong EF2 wedge tornado which caused significant damage to the school campus. Students and faculty were relocated and finished the remainder of the 2012 school year at the former Shaw Junior High School in west Mobile while the Murphy campus was rebuilt. On August 19th, the renovated storm damaged high school campus reopened. 
^ abThomason, Michael. Mobile : the new history of Alabama's first city,pages 260-261. Tuscaloosa : University of Alabama Press, 2001. ISBN 0-8173-1065-7
^United States Department of Health Education and Welfare (DHEW) Office for Civil Rights, Directory of Public Secondary and Elementary Schools in Selected Districts: Fall 1970, U.S. Government Printing Office, Washington, D.C., 1972, p. 16.