The history of the Center City Neighborhood is, to a large extent, the history of Wichita because the City began in what is now the Center City Neighborhood. In 1865, the Osage Indian Tribe ceded more than four million acres of land to the United States. Settlers quickly occupied much of the land and began applying to the state to incorporate towns. The City of Wichita was incorporated in 1870.

Darius Munger and William Griffenstein combined their plats to form the town. Central Avenue became the dividing line between the two plats and would remain important as a highway connecting Wichita to El Dorado. The north-south streets of the two plats lined up, but they had different names on either side of Central Avenue. This was rectified in 1889.

Shortly after the founding of the town, the primary business district shifted from Main Street to Douglas Avenue just south of what would become the Center City Neighborhood. Douglas Avenue has remained an important commercial street.

Development of the Center City Neighborhood began almost immediately as the population of Wichita increased. By 1887 the population topped 31,000 residents. At this time, several of the most prosperous residents moved from the Center City Neighborhood to the more prestigious neighborhoods of Riverside and College Hill.

With the growth of the city came the need for quality medical care. Dr. Andrew Fabrique founded St. Francis Hospital in 1886. Three years later the Sisters of the Sorrowful Mother assumed responsibility for the hospital. The Sisters added the first hospital expansion, increasing the facility from 15 to 60 beds, in 1896. Expansions have continued throughout the hospital's 110-year history with the most recent completed in 1993. The hospital now employs nearly 4,000 persons.

The year after the opening of St. Francis Hospital, a ten-year drought began. While much of the state lost population, Sedgwick County gained population as farmers moved out of the harder hit rural counties of Kansas.