The lifeless pampas around Iquique is peppered with the geoglyphs of ancient indigenous groups, and the shelf where the city now lies was frequented by the coastal Chango peoples. However, the Iquique area was first put on the map during the colonial era, when silver was discovered at Huantajaya.

During the 19th century, narrow-gauge railways shipped minerals and nitrates through Iquique. Mining barons built opulent mansions, piped in water from the distant cordillera and imported topsoil for lavish gardens. Downtown Iquique reflects this 19th-century nitrate boom, and the corroding shells of nearby ghost towns such as Humberstone and Santa Laura whisper of the source of this wealth.

After the nitrate bust, Iquique reinvented itself primarily as a fishing port, shipping more fish meal than any other port in the world. However, it was the establishment of the zona franca in 1975 that made this one of Chile's most prosperous cities.