[3] The origins of Città Sant'Angelo are uncertain and have always been a basis for historical discussion, beginning with the Vestini, an ancient Sabine tribe.

The numerous archaeological finds between the mouths of the Piomba and Saline Rivers, and the presence of small urban settlements at the site called Marina Sant'Angelo point to the origins of the town during the Roman period, located in the eastern portion of the Vestine region.

The vestino-roman habitations, which would have been located in the nearby Salt Hill, were probably destroyed in the early Middle Ages, during the Gothic War (535–554); the Longobards (Lombards) who invaded Italy after the Gothic War, would likely have rebuilt the areas from scratch in their present locations, leaving as the trace of their later presence the veneration of the archangel Michael.

It was a Guelph town, destroyed in 1240 by Boemondo Pissono, executioner to Frederick II, Holy Roman Emperor of the Hohenstaufen dynasty, and successor to the Normans as the King of Sicily, because the city was too loyal to his enemy, the Catholic Church.

In March 1814, Città Sant'Angelo, together with the municipalities of Penne and Castiglione, formed the setting for the first ups and downs of Carboneria of the Italian Risorgimento, where Messer Raimondo and Penna Sant'Andrea were the protagonists.

The revolt was repressed by the troops of Gioacchino Murat, led by General Florestano Pepe, thanks to the betrayal of a conspiracy and the turnaround by several municipalities that had pledged their support but eventually remained silent.

During the Second World War, in April 1940 the Ministry of the Interior set up and rented the building of the Ex Manifattura Tabacchi, in the historic centre of the city, to serve as the only concentration camp of the province of Pescara, holding about 200 prisoners from Yugoslavia.

On May 22, 1944, the US Air Force bombed the marina district; seventeen from Città Sant'Angelo lost their lives, in addition to German soldiers.