Clay Arsenal is one of Hartford's oldest neighborhoods, developed in the middle and late 19th century. It was mainly farmland prior to 1847, when the Hartford-Springfield Railroad, which now forms the neighborhood's eastern border, was constructed. At one time, Windsor and Main streets intersected just north of Downtown. When the streets were reconfigured, several buildings an a public green were lost.

The section west of Main Street lies on a gentle rise above Downtown and is known as Clay Hill, so named for the type of soil there. The area east of Main Street has been known since 1812 as the Arsenal District, when a State Arsenal was constructed on the corner of North Main and Pavillion streets. The Arsenal was demolished in 1909.

The mid-19th century development of the Clay Hill area from rural to urban conditions was caused by the strong industrial growth of the city. As the city's factories rapidly grew more successful, the community at large was forced to keep up. The changes took the form of converting the farm land of long time residents to city streets for new home owners.

Multi-family dwellings were the dominant development in the late 19th century as the neighborhood became home to Irish and Jewish working class families. The Irish had been emigrating to Hartford through a recruitment effort for work on the Enfield Canal in Windsor Locks. In 1895, Clay Hill was predominantly Irish and was served by Saint Patrick's church in downtown Hartford.

At about the same time, large numbers of Jews began arriving from Eastern Europe due to the anti-Semitic sentiment there. The new emigrants established themselves in the Arsenal district as grocers, tailors, butchers and jewelers along Main Street and Albany Avenue.

Although he area has been primarily residential, in the post-Civil War era, the railroad attracted businesses, including a lumber yard, brewery and carriage works. Additionally, the Hartford County Jail was built in 1873 on Seyms Street. Designed by Hartford architect George Keller, it embodied the High Victorian Gothic style. The structure was demolished in 1978.

The Marietta Canty House on Mahl Avenue was the home of actress Marietta Canty (1905-1986), who received critical acclaim for her performances in theater, radio, motion pictures, and television as well as her political and social activities. Built c1897, the home was built by developer Frederick Mahl, and was added to the National Register of Historic Places in 2000.

The African-American community grew significantly during World War I when large numbers of southern blacks were hired to work the tobacco fields and sheds in the state's booming shade tobacco industry. After World War II, the area began to see a growing number of Puerto-Rican families, many of whom came to work the tobacco fields. The sequential change in the ethnic character of the residents of the district is illustrative of social history in Hartford. Original Yankee farmers were followed by Irish, German, Jewish, Black and Hispanic peoples as immigrants found their place in the community and sought upward mobility, often in trying circumstances. A significant portion of the neighborhood today are Latinos who have created a strong community of residents, churches, businesses and institutions.

The SAND Elementary School opened its doors in 2009 as part of the America's Choice model. It serves grades K–8. A community library and community resource center housed in the same facility expands the opportunity for educational advancement and sociald evelopment for students, parents and residents alike.

Mary Shepherd Place was formerly known as Bellevue Square. Built in 1942, the development underwent a multi-million dollar overhaul in the late 1990s to include apartments, townhouses and a community building. Families who reside there must pass through a background screening and participate in self-sufficiency training.

The neighborhood is also the site of both Old North and Saint Patrick's cemeteries. Originally called the North Burying Ground, the cemetery was established in 1807 and represents a cross-section of 19th century Hartford society, including Jewish and Italian immigrants, Civil War soldiers and prominent residents (more). Saint Patrick's Cemetery is closely aligned with Saint Peter's Church in Hartford.

The Clay Hill Historic District spans roughly 60 acres of the neighborhood and contains examples of Italianate, Queen Anne and Neo-Classical Revival styles of architecture.

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