E. Rossoni notes that this surname is very widespread throughout the peninsular south and in Sardinia. According to Rossoni, most of the variants —Mele, Meli, Melì, Melle, Melli, Mello, Mellon and Melon— would derive, directly or through augmentative forms, from the medieval name Mele ("honey"), frequently given to a much-wanted child. In Logudorese Sardinian mele and in Campidanese meli mean "honey", from the Latin mel - mellis and the Greek méli. Rossoni warns, however, that in the Italian peninsula Mele may derive from the Italian mela ("apple", from the Latin malum), and Meli from the Italian melo ("apple tree", from the Latin malus).

Among the variants, Meli shows specific areas in Sicily, Sardinia, Rome, the province of Florence and that of Parma; Melli shows two clusters, one in the Milan area and another between Mantua and Modena; Mello appears to originate in the Salento area —the southernmost zone of the region of Puglia, in southern Italy—; and Melon is proper to north-eastern Italy, in the regions of Veneto, Friuli-Venezia Giulia and Trentino-Alto Adige.

E. De Felice, by contrast, reads the surname as of Genoese origin, formed from the place name Méle, in the Genoa area, without linking it to the etymology of the noun "honey".