The monument was probably built in the 2nd century AD. The exact date is uncertain, but the architectural style suggests some time between the Emperors Hadrian and Antoninus Pius. It seems clear that it was expanded in the 3rd century AD, tripling the structure's size.[1]

A baseless popular legend claims that lava flows from the eruption of Etna in 252 reached the theatre but did not destroy it. This tradition derives from the life of Saint Agatha as reported in the Acta Sanctorum of Jean Bolland, where it is reported that in the specific year of the saint's death (251) lava flowed towards the gates of the city and the farmers, worried for their fields, went to the tomb of the saint, removed her funerary shroud and used it to stop the lava. Although this source is obviously hagiographical, it led vulcanologists like Carlo Gemmellaro to erroneously interpret the amphitheatre (which is near the city gates) as the point where the lava stopped. Recent stratigraphic studies have clearly shown that the rock identified as the 'lava flow of Saint Agatha' of 252 actually came from Monpeloso and flowed through the area of Nicolosi before cooling and solidifying in Mascalucia, about 450 metres above sea level. Thus, it moved toward Catania but never actually reached it.[2] The sole traces of lava near the amphitheatre are a lava ledge which abuts one of the vaulted walls of the building. However, when a core was drilled into the walls of the internal walkway in the twentieth century in order to determine what was behind them, "wagonloads" of liquid flowed out,[1] clearly indicating that the space behind is empty. The fragment of volcanic rock is very likely fill placed there in order to support the foundations of the facade of the Chiesa di San Biagio above it.

 Panoramic view of the inscription installed on the excavated amphitheatre per me civitas catanensium sublimatur a Christo (Through me, the City of Catania is raised up by Christ), a statement attributed to Saint Agatha, who is meant to have been martyred nearby.

According to Cassiodorus, in the 5th century, Theodoric, King of the Ostrogoths, allowed the inhabitants of the city to spoliate the theatre for building material for the construction of stone buildings,[3][4] on the grounds that the monument had been abandoned "for a long time."[3] According to some authors, Roger II further spoliated the structure in the 11th century for the construction of Catania Cathedral, including the grey granite columns that decorate the cathedral's facade and the apses,[5] in which perfectly cut stones can be seen,[6] which may also have been used in the construction of the Castello Ursino in the Swabian period.

In the 13th century, according to tradition, the amphitheatre's vomitoria (entranceways) were used by the Angevins to enter the city during the Sicilian Vespers. In the following century, the entrances were walled up and the ruins were incorporated into the Aragonese fortifications (1302). In 1505, the civic senate granted Giovanni Gioeni a concession to use the monument's stone for the construction of houses and to use the arena itself as a garden.[6] Measures were taken to secure the ruins in the construction of new fortifications in 1550: the first and second stories were knocked down and the galleries were filled in with the rubble. After the 1693 Sicily earthquake, it was finally buried, and the area was turned into a parade ground. Subsequently, the extrados of the galleries were used as the foundations of new houses and for the Neo-classical facade of the Church of San Biagio.

From the second half of the 18th century, the amphitheatre was the object of archaeological excavation. However the discoveries were not preserved: instead the arches were walled up and reused in the buildings of the reconstructed city. In the early years of the 20th century, renovation work was undertaken in order to open the site to visitors, as part of the construction of the Piazza Stesicoro. In 1943, during the allied bombardment which reduced parts of the city to rubble, the structure was used as a bomb shelter. Subsequently, it experienced periods of interest and abandonment. For several years, the tunnels were kept shut for 'security reasons', following tragic accidents resulting from people exploring. The amphitheatre was renovated in 1997 and opened that summer. Then it was closed due to the influx of sewerage from the neighbouring houses. This was partially fixed and it was reopened to the public in 1999, but then closed a little later as a result of its deterioration.

The remains, representing about a tenth of the amphitheatre, are visible from the entrance of the Piazza Stesicoro and from the Vico Anfiteatro, where the structure is visible up to the third floor. Until 2007, it was possible to see part of second story on the Via del Colosseo, but it is now entirely covered by the new terrace of the Villa Cerami. Inside the villa, which is now used by the University of Catania's Faculty of jurisprudence, it is still possible to see part of the vaulting system that linked the Amphitheatre to the Montevergine hill (probably the ancient acropolis of the city). The rest of the amphitheatre is below the Via Neve, Via Manzoni, and Via Penninello.

The early modern excavations seem to be the reason for the instability of the structure, which was announced in 2014 to be in danger of collapse in a parliamentary debate and which had already been brought to public attention by CTzen.[7] On 24 April 2014, an expert board was established in order to organise the recuperation of the monument and to safeguard the neighbourhood which has developed on top of the structure over the centuries.[8]