At the time of the Spanish conquest, Santa Ana was inhabited by the Pipils who called the area Sihuatehuacán. In July 1569, the Guatemalan bishop Bernardino Villalpando officially named the city Santa Ana.

Just south of Santa Ana, Parque Nacional Los Volcanes encompasses three major volcanos - Cerro Verde, Volcán Izalco and Volcán Santa Ana - and a large area in the heart of the country. Cerro Verde is the oldest: it formed 1.5 million years ago and hasn't erupted in 25,000 years. Volcán Izalco is the youngest - in fact one of the youngest in the world. Before February 1770, there was nothing but a hole in the ground from which columns of black sulfuric smoke would occasionally rise. Then it started burping rocks and lava, and a cone began to form. The park's largest volcano, Volcán Santa Ana (aka Mother Hill), last erupted in the late 19th century.

Construction of Alcaldía Municipal de Santa Ana, Santa Ana's beautifully colonial city hall, began in the 1870s. It replaced the first city hall, which was destroyed during a peasant's revolt, and took 53 years to build.

Volcán Izalco continued to erupt into the 20th century, earning it the reputation of 'lighthouse of the Pacific'. In 1957, after erupting continuously for almost two centuries, it stopped. It has only hiccupped once since, in 1966, but is still considered active.

Santa Ana's theatre, Teatro de Santa Ana, was constructed with funds from an export tax on coffee beans. It opened its doors in 1910, and was the symbol of wealth and high culture in the west. Sweeping marble staircases, stained-glass windows, parquet floors and bronze statues of Roman gods - it even opened with the opera 'Rigoletto', which was performed by an Italian opera company. In 1933, the theatre was converted into a movie house. It quickly deteriorated, however, with fixtures and artwork disappearing - even the curtain was stolen - and remained in disrepair until 1979, when Santa Ana residents decided to renovate.

Construction of the city's neo-Gothic cathedral, Catedral de Santa Ana, began in 1906 and was completed in 1913. Additional work, however, continued over the decades until a marble altar to the Virgin Mary was consecrated and completed in 1959. The Gothic style of the cathedral was intended to contrast the predominantly Spanish colonial style of most of El Salvador's cathedrals. The North Tower features three manually activated bells, while the South Tower has three electronically activated bells which were shipped in from the Netherlands in 1949.

At the turn of the century, the coffee market took the main stage from indigo in El Salvador. Many wealthy crop owners lived in Santa Ana, making it one of the most prosperous cities in the country.

In October 2005, Volcán Santa Ana awoke dramatically, spewing rocks, ash and gas but, thankfully, no lava. Landslides triggered by the eruption killed two coffee pickers and forced the evacuation of thousands. The ash, which rose in a cloud thousands of meters high, later fell with the late-winter rain, blanketing large areas with sulfurous mud and killing many coffee trees.

More than 25 years after renovations began, Teatro de Santa Ana is 80% finished. Original items such as statues, chandeliers, chairs and the curtain have been recovered; the facade has been repainted and murals have been restored. Cultural events, including concerts and plays, are held weekly and tours are available.