The Clark-Fulton neighborhood was first settled by German immigrants during the mid-nineteenth century. The Germans were followed by Czechs, Italians, Slovaks and Poles. These immigrants were attracted to the area to work in the nearby industries in the Flats as well as the breweries that developed along Train Avenue. Originally park of Brooklyn and Newburgh Townships, portions of the area were annexed to Cleveland in 1867 and 1873.

Commercial districts in the Clark-Fulton area developed during the late 19th and early 20th centuries to serve the growing immigrant population. Businesses flourished principally along Pearl Street (today West 25th Street) and Clark Avenue. To the north and south of Clark Avenue, the single- and two-family residences that characterize the neighborhood today date principally from the late 19th century.

The Scranton Road portion of the neighborhood is dominated by the MetroHealth Medical Center, which was established at its present location in 1889 as the City Hospital. As a result of several major expansions, the hospital has grown to encompass a 42-acre campus.

Physical development patters in the Clark-Fulton area were also changed dramatically during the 1960's and 1970's by the construction of I-71 and I-90. These highways act to separate and isolate the neighborhood from surrounding areas. In recent decades, the neighborhood, along with other portions of the near west side, has become home to much of Cleveland's Hispanic community.