Agricultural products grown in the villae nearby and valuable minerals (silver, gold and tin) obtained from the lower Alentejo region were sent from the fluvial port of Mértola via the Guadiana to Southern Hispania and the Mediterranean.

Between 1st and 2nd century, Myrtilis, was part of the larger Pacensis region (under the capital Beja/Pax Julia), acquired a great importance, as a dynamic commercial centre, permitting it to mint its own coin.

Between 1144 and 1150 the town was again seat of an independent state led by Ibn Qasi, a mystic and skilled military leader who unified Southern Portugal and fought the power of the Almoravides.

The most important remnant from the Islamic period in Portugal is Mértola's ancient mosque, built in the second half of the 12th century and later turned into a church, but keeping original architectural characteristics.

In 1238, in the context of the Reconquista, the town was conquered by Portuguese King Sancho II, putting an end on several centuries of Islamic rule in the Mértola region.

From the Reconquista time date most of the castle, including its mighty keep, and a letter of feudal rights (foral), granted in 1254.The economic importance of Mértola and the Guadiana faded after that period.