Vila Real de Santo António (pronounced [ˈvilɐ ʁiˈal d(ɨ) ˈsɐ̃t(u) ɐ̃ˈtɔnju] ⓘ) is a city, civil parish, and municipality in the Algarve, Portugal.

Before the construction of the Guadiana International Bridge (in its neighboring upstream municipality of Castro Marim), it used to be the easiest access to Portugal from Andalusia (via ferry from the Spanish city of Ayamonte across the river).

Small settlements were eventually established near the Cacela, including many medieval fishing villages, such as Santo António de Arenilha along the coast.

The impetus for this decision is unclear, but there was several justifications for enhancing the settlement of the region, which included: increasing the human presence near the Spanish border, to prevent any incursions; to better control duties charged on cross-border activity; to be better defend the region from a full-scale attack; or to provoke Spain with a modern settlement that was easily seen from Ayamonte; or to simply rebuild the nearby town fishing village of Santo António de Arenilha and resettle its population.

Santo António de Arenilha was destroyed by the same tsunami that was triggered by the devastating 1755 Lisbon earthquake.Regardless, the settlement was erected at great speed for the time (in only two years) and completed in 1776 using the latest technologies.

Along the river, the customhouses (Portuguese: Alfândega), was one of the first buildings to be completed during the Pombaline reconstruction, to house the offices of the Sociedades das Pescarias (fishing associations/societies), and dividing the settlement in two.

As the first canned fish undertaking in the country, the Vila Real de Santo António plant of Conservas Ramirez is the cradle of the sector in Portugal.

Vila Real de Santo António thrived on the growth of the fishing industry, which included the processing of species of tuna and sardine.

The establishment, in 1975, of the Castro Marim and Vila Real de Santo António Marsh Natural Reserve provided a refuge for several species of migratory and marine birds, namely mallards, flamingos, Kentish plovers, little terns, pied avocets, dunlins, stilts, white storks, and spoonbills, while at the same time protecting breeding grounds for local fish and crustaceans.

Vila Real de Santo António has a Mediterranean climate (Köppen: Csa) with short, mild winters and hot, dry summers.

Several artists were born and/or worked in Vila Real de Santo António, providing a rich heritage in literature and visual arts.