In the precolonial era, the Tongva people lived in as many as 100 villages and primarily identified by their village name rather than by a pan-tribal name. The Tongva called the Santa Ana area "Hotuuk."

According to apocryphal Christian and Islamic tradition, Saint Anne was the mother of Mary and the maternal grandmother of Jesus. Mary's mother is not named in the canonical gospels. Anne's name and that of her husband Joachim come only from New Testament apocrypha, of which the Gospel of James (written perhaps around 150) seems to be the earliest that mentions them. The mother of Mary is mentioned but not named in the Quran.

Before Santa Ana became an actual city in 1869, it was a mustard field sitting in the middle of nowhere. The mustard field became a town when founder William H. Spurgeon bought 74 acres from the Yorba estate for $595 and began to lay out a 24-block village. Spurgeon set aside an entire city block for construction of an impressive stone courthouse with a tower that rose higher than any building in town and still stands today.

The Santa Ana winds are known for the hot, dry weather that they bring, often the lowest relative humidities of the year. These low humidities, combined with the warm, compressionally-heated air mass, plus high wind speeds, create critical fire weather conditions. Also sometimes called "devil winds", the Santa Anas are infamous for fanning regional wildfires.

Based on the low number of violent crimes and traffic fatalities, Forbes ranked Santa Ana the fourth-safest U.S. city of over 250,000 residents in 2020. (First on the list of safest cities is Plano, Texas, followed by Henderson, Nevada, and Honolulu, Hawaii.)

Joseph Prentice donated land for the zoo in 1949 with the stipulation that the city must keep at least 50 monkeys at all times. To this day, the zoo maintains an extensive primate collection with over a dozen species from around the world.

According to data from 2017, 76.5% of Santa Ana residents are Hispanic. Just over 11% are of Asian descent, and around 10% are Non-Hispanic White.

Santa Ana is the county seat and has always fancied itself the center of Orange County. In 2006, city officials spent more than $1 million to refurbish a water tower next to the 5 Freeway and paint it with a new slogan: DOWNTOWN ORANGE COUNTY.

Lying south and east of the city of Santa Ana, the mountains rise to their highest point at Santiago Peak, an elevation of 5,687 feet (1,733 metres). More than one trail leads to the top of Santiago Peak, but due to the large number of antennas at the summit, a full 360-degree view of the surrounding landscapes is not possible.

The Santa Ana River is 96 miles (154 km) long, and its drainage basin is 2,650 square miles (6,900 km2) in size, making it the largest river located entirely within Southern California.