E. De Felice considers that this surname derives from the appellative and honorific title sère (from the Latin senior: "old man"), widely used from the Middle Ages to the Renaissance, above all in its reduced unstressed form ser, placed before the name of priests, notaries, high officials and notable persons (such as ser Andrea, ser Angelo, and so on). In its base form it is very rare; its compounds appear with medium or low frequency in Veneto, Emilia-Romagna, Tuscany and central Italy.

E. Rossoni proposes, on the other hand, that the surname would derive from the medieval name Serius, a contracted form of Sigerius, documented in 1171 in the Annales Pisani. According to Rossoni, Seri is characteristic of eastern Tuscany, the region of the Marche, the Terni area, the Rieti area and especially the Rome area; while the variant Serio is very diffused in Campania —especially in the Salerno area—, in Apulia and in Sicily.