In 1266 Manfredi was defeated in Benevento by Charles of Anjou, who came to Italy with the blessing of the Pope, precisely to stop Manfredi. The loyalty of the city of Salerno to the Swabians, with the commitment of Giovanni da Procida in organizing the resistance, provokes the harsh reaction of the Angevins, and leads to destruction, abuse, oppression and devastation to the city.

The Salerno society was able to express a fair vitality, thanks to some structural characteristics of the city, starting from a natural function of mediation - by virtue of its happy geographical position - between the rich hinterland of the Principality and the capital, to which it was the pendant is a notable vocation for craftsmanship and retail trade, which also developed as a result of the immigration phenomena that affected Salerno starting above all from the 11th century. However, Salerno's range of action remained substantially limited - as elsewhere in the South - due to the absence of a merchant "class" capable of operating on broad economic and financial scenarios, despite the city hosting one of the most important trade fairs in the continental South. , around which a considerable turnover of business, kingdoms and sovereigns moved.

But Salerno continues to play a significant role in the royal context, thanks also to the fact that it has an important port and of being home to one of the largest fairs in the South, frequented by royal and foreign merchants: both structures will continue to be functional in the following centuries. With the Angevins, the city became the center of the new political entity, the Citra Principality, created at the end of 1200 and it kept an economic, social and political supremacy on this territory for a long time thanks to the vast district, the large diocesan territory, the social dynamism, an economic facies that found its strengths in the port and in the fair established by Manfredi, as well as in the function of geographical connection between Naples and the Calabrie, its particular proximity to the capital. However, his political role, which was substantially maintained during the Norman-Swabian era, was permanently decreasing, to give progressively way to Naples, which just with the Angevins would have become the real heart of the South, relegating the other cities – even the ones with an illustrious history as Salerno – to the rank of suburbs of the Kingdom.

Even 14th century Europe was not an easy time to live in. The harvests failed in 1315, and the same thing happened again in 1316. The result was widespread famine. It was only in the summer of 1317 that the weather allowed for the growth of crops. This event became known as the Great Famine of 1315-1317. The year 1347 was when the bubonic plague, or the Black Death, was at its peak, and it was truly a terrible time to be alive. Over the course of eight years, it is estimated that about 200 million people died, which was about 60% of the European population..

During the Angevin period, the famous doctor Matteo Silvatico lived in Salerno, known to Boccaccio who wrote a short story (X of the 4th day) in which there is a Salerno doctor named Mazzeo della Montagna, clearly inspired by him. Matteo Silvatico is the founder of what is now called "Giardino della Minerva", a splendid botanical garden restored according to the principles of medieval medicine.