The early history of the city was that of its first inhabitant, Juan López, better known as "Chango López", who began his exploration of the area in 1845, searching for guano and copper mines.

In 1871 it was given the name of Antofagasta and was designated a major port. The city was involved in the Pacific War when it was occupied by Chilean troops on February 14th, 1879.

By 1900 there was already much activity in the port, and this resulted in the construction of several buildings to serve a variety of functions, such as the Maritime Authority building and the Customs House. Many of them have been declared National Monuments for their architectural merit.

The growth of this area was based on its seafood and fish, but more importantly on the exploration and extraction of mineral resources. In the nitrates era the region reached its apogee, and this also helped to develop tourist interest in the coast north and south of the city. So it was that the last years of the 20th Century were marked by rapid economic growth, particularly notable for the creation of the infrastructure for the extraction, transport and shipping of mineral resources, including the construction of the railway and the port.

During the 20th Century it experienced accelerated growth, displacing Iquique as the main port for nitrates shipments.

Today, Antofagasta is considered to be the economic and cultural capital of the north of Chile.