Villa Mitre was developed on land originally purchased by Francisco Ruiz de Gaona during the late colonial era, and he lived there until his death in 1813; Gaona Avenue, located along the ward's southern border, was named in his honor.

The land was later subdivided into smallholdings mainly devoted to alfalfa, horticulture, and brick kilns.

The neighborhood remained prone to flooding until work began in 1929 on converting the Maldonado Stream into an underground storm sewer, above which Juan B. Justo Avenue was inaugurated in 1936.

A block-sized lot adjacent to the Cabrini Institute was purchased by the City Government in 1937 to create Sáenz Peña Square, the neighborhood's largest park.

Diego Maradona Stadium, home venue for the Argentinos Juniors football team, was inaugurated in Villa Mitre in 2003.