The municipality of Alfiano Natta lies on the southern slope of Montebaldo hill, with its upper section shaped by the basin of the Versa stream. In the 18th century, Giovanni Giacomo Saletta described “Alfiano, Sanico, and Casarello” as being “in Monferrato, between the Po and Tanaro rivers, on the borders of Villadeati, Tonco, Caliano, and Moncalvo.” Today, the neighboring municipalities also include Castelletto Merli, Odalengo Piccolo, and Penango.

The name appears in early documents as Alfianum, a form that remained unchanged until the 14th century. In 1863, “Natta” was added, in reference to the noble family that held the fief from 1483 onward.

Alfiano belongs to the Diocese of Casale Monferrato, and its parish church is dedicated to Saint Marziano.

Historically, the domain of Alfiano, together with Sanico and Casarello, was granted in fief by the Marquises of Monferrato to the Alfiano Guala family. After the extinction of that line, William II of Monferrato assigned it ad personam to Secondo Visconti (1515), who later transferred Alfiano and Sanico to the Natta family (1531). The Nattas remained lords of the area until their line died out in 1866.
As part of the Marquisate and later the Duchy of Monferrato, Alfiano came under the Savoy in 1708, joining the province of Casale. This structure remained until 1798, when the old regime in Piedmont fell. Under Napoleonic rule, Casale was incorporated into the district of Alessandria—first in the Department of Tanaro (1799), and later, following the administrative reform of 1801, in the Department of Marengo, arrondissement of Casale. After the Restoration, Alfiano Natta once again became part of the reconstituted province of Casale, included in the division of Alessandria. In 1859, this was reduced to the district of Alessandria, where Alfiano Natta still belongs today.

A curious episode from its history is the dispute of 1762–1763 between Alfiano and Odalengo Piccolo over ownership of the wooded area known as Carpegna.