It was founded about two thousand years ago; across its history it was first governed by the Exarchate of Ravenna, then by the Duchy of Ferrara, and eventually returned to be part of the territories of the Papal States.

The wetlands south of the town, the Valli di Comacchio, are classified as a Site of Community Importance and a Special Protection Area in Italy.

[4] The etymology of the town's name is uncertain (Greek-Latin cumaculum meaning "small wave"; "grouping of bumps" in Etruscan).

After its early occupation by the Etruscans and the Gauls, when the site lay on the main stream of the River Po, Comacchio was annexed by Rome.

The area was the scene of fierce fighting during Operation Roast, which occurred in the last months of the World War II.

The town is noted in Italy for its practice of eel-fishing in the nearby wetlands, and many dishes served in Comacchio revolve around eel.

In the past, salt production was also very important, whose trade had been causing bitter disputes with the Serenissima Republic of Venice.