The territory was Roman and agricultural from the start. Villas survive in the countryside, and where the sanctuary of the Madonna di Ripalta now stands there was a temple to the goddess Bona . An inscription found here names a curator , Lucio Publilio Celso Patruino , probably of Herdonian family — and the settlement itself seems to have been a grain depot with an attached mutatio , a posting station dependent on Herdonia. Two thousand years later the town's principal monument is still a grain store.

A settlement of around 300 BC called Cerina or Kerina may lie beneath it, and the place developed as a municipium under Rome. The first document to name the city is in the Codice diplomatico barese , dated 1150 , which mentions a domum Malgerii Cidoniole . Under the Angevins its position on the ancient Via Traiana brought real agricultural and commercial growth, and in 1418 it became a fief of the Caracciolo .

On 28 April 1503 Cerignola — then a borgo of about 350 families — became the site of a pitched battle for the possession of southern Italy. The Spanish under Gonzalo Fernández de Córdoba , the Gran Capitán, faced the numerically stronger French under Louis d'Armagnac, duke of Nemours . Córdoba had studied the ground carefully and marched almost secretly to reach it before the French, despite losing men to heat and drought on the way. Nemours was killed, the French were broken, and the Kingdom of Naples passed definitively to Spain. The contrada where the decisive fighting happened was afterwards renamed the Tomba dei Galli , the tomb of the Gauls. The townspeople, by the local account, celebrated with the Spanish soldiers.

The town's continuity was then broken by the ground. In 1731 an earthquake destroyed almost the entire medieval borgo — the Terra Vecchia — which is why Cerignola's early history is described by its own historians as uncertain, and why so much has to be reconstructed from inscriptions and archaeology. The ancient Porta della Terra and its clock tower survived until they were pulled down in 1805 .

The modern town is a nineteenth- and twentieth-century creation on a grain economy: the Duomo Tonti , one of the largest churches in Puglia; the Teatro Mercadante ; Palazzo Carmelo; and out in the countryside the Torre Alemanna , the tower of a commandery of the Teutonic Order, at Borgo Libertà. A Roman milestone from the Via Traiana still stands in the town.

Two men gave Cerignola a place in wider Italian history. Pietro Mascagni was the town's bandmaster and composed Cavalleria Rusticana here. And Giuseppe Di Vittorio was born here — the labourer who became the most important trade unionist in twentieth-century Italy. The peasant struggles he led on this land won greater rights for agricultural workers, including the famous fifty per cent for sharecroppers, and established the role of the union in Italian public life. In a town of braccianti , that is not a footnote; it is the central fact of its modern history.