The San Diego River valley was originally called La Cañada de San Diego. Cañada in Spanish means gully, ravine, or glen. The name was changed to Mission Valley in the 1860s in reference to Mission San Diego de Alcalá. The Mission Valley area was inhabited by Kumeyaay Indians for more than 10,000 years. The first Spanish settlement in present-day California was the Presidio of San Diego and Mission of San Diego de Alcalá, both established in 1769. The Presidio and Mission were located at the western end of Mission Valley, present day Old Town, where the valley opens out into the flood plain of the San Diego River. In 1774 the Mission was moved to its present location at the eastern end of Mission Valley because of better access to fresh water for drinking and farming. Until the 1940s Mission Valley remained largely undeveloped, featuring dairy farms and other agricultural activities; the city of San Diego was largely confined to areas south of the valley. After World War II the city’s expansion began to encroach on the valley. The last of the valley’s dairy farms closed in the early 1960s.

Another early activity in Mission Valley was quarrying sand and gravel from its walls. A large quarry on the north side of the valley was in operation for most of the 20th century. The quarry ceased operation around 2000 and is now the site of the Civita mixed-use development. The development of Mission Valley began in 1953 when the first hotel was built in what is now Hotel Circle. In 1958, the city council rezoned 90 acres of the river valley to allow construction of San Diego’s first regional shopping center. The Mission Valley Center (now Westfield Mission Valley) opened in 1961 and was followed by several other large regional shopping malls. In the late 1950s and early 1960s, the U.S. 80 freeway (now Interstate 8) was constructed through Mission Valley, further opening the area up for development. Westgate Park, a baseball stadium for the then-minor-league San Diego Padres, was built in Mission Valley in 1957. In 1967 San Diego Stadium (later renamed Jack Murphy Stadium, now Qualcomm Stadium) was opened and the Padres moved there, becoming a major league team the following year. Westgate Park was razed in 1969 and was replaced by the Fashion Valley Mall.