The city was named after the nymph Amphissa, daughter of the mythical king Makar, son of Aeolos. Built on a strategic location on the foothill of Mt. Giona, Amphissa is mentioned by Strabo and Pausanias. It was a  Locrian city which thrived in the Classical, Hellenistic and Roman period.  

The earliest habitation of the city dates to the Geometric period. The acropolis and its fortifications dominate the modern city. In antiquity, Amphissa entered in a famous rivalry against the Delphic Amphictyony for the control and cultivation of the Krissaean plain; during the Peloponnesian War it sided with the Spartans. 

In the 4th century B.C. many clashes occurred in the region of Amphissa because of the wealth accumulated within the Delphic sanctuary. The Fourth Sacred War resulted in the destruction of the city by Philip II in 338 B.C. The city was subsequently rebuilt, regenerated and it fought along with the other cities of the Aetolian League against the Galatians (279 B.C.) and the Romans who besieged it to no avail in 190 B.C. 

After Octavian's victory at Actium, Amphissa hosted a number of Aetolian refugees and continued to thrive up to the Frankish period. Then, it became part of the kingdom of Thessaloniki and seat of the Barony of Salona (La Sole) under the rule of the French noblemen D'Autremencourt and subsequently of the Catalan Society. In the Ottoman period Salona was the seat of a kaza, i.e of an administrative district. When the Greek War for Independence broke out in 1821, the Greek Orthodox inhabitants revolted and killed the Ottomans who dwelled within the castle.  In the broader region had their headquarters important Revolution leaders, such as Panourgias, Dyovouniotis, Gouras, Athanasios Diakos and the Bishop of Salona, Isaias. In 1826 Salona was reconquered by Kütahi Pasha, who was eventually forced to hand it over to Dimitrios Ypsilantis three years later. After the liberation, many Ottoman buildings were demolished. The town planning and architecture of the city was further affected by the earthquake of 1870. However, there are still some houses and fountains to remind us of the Ottoman past of the city. 

In Amphissa have taken place many excavations which have revealed parts of the classical, Roman and Late Roman city. The finds are exhibited in the Archaeological Museum of the city.