Main Street's route was established in the 14th century which was confirmed when the Puerta de África (now called the Southport Gates) were built in 1575, during the Spanish period.

Nearly every building on Main Street was damaged during the Great Siege of Gibraltar when from 1779 to 1783 the town was attacked by a combined French and Spanish fleet.

Col. John Drinkwater wrote: Some few [houses], near South-port, continued to be inhabited by soldiers families; but in general the floors and roofs were destroyed and the bare shell only was left standing.

[3] It runs north–south through the old town which is pedestrianised and lined with buildings displaying a blend of Genoese, Portuguese, Andalusian, Moorish and British Regency styles,[3] most of which have shops on the ground floor.

[3] Grand Casemates Square at the northern end of Main Street, once the centre of public executions, is the hub of Gibraltar's nightlife, and is filled with numerous restaurants, pubs and bars.