The authors agree that this surname may derive from the personal name Sesto (feminine form Sesta), linked to the ancient Latin praenomen Sextus, "sixth," attributed to the sixth child of a family. It may also come from place names containing the root Sesto, frequent throughout Italy, especially in the north and the centre, originally used to designate localities situated at the sixth mile from a larger centre.

E. De Felice notes that from these place names would have arisen, as demonym forms, variants such as Sestani or Sestan, proper to the north-east of Italy, in the regions of Veneto, Friuli-Venezia Giulia and Trentino-Alto Adige, and that the variant Sestini is linked with the region of Tuscany.

E. Rossoni specifies that among the place names of possible origin stand out Sestino, in the Arezzo area; Sesto San Giovanni, in the Milan area; and Sestu, in the Cagliari area. He indicates that Sesti presents zones in Lombardy, in Tuscany —in the Florence and Arezzo areas— and in Calabria, in the Cosenza area. He adds that Sestini is typically Tuscan, with a presence in the Florence, Arezzo and Siena areas, while Sestu, of Sardinian character, is concentrated in southern Sardinia.