E. Rossoni notes that the surname would derive from the Late Latin name Guiso (in its extended form Guisone), documented in the Codex Cavensis under the year 956 and in a deed of sale of 1025. According to another hypothesis that Rossoni also records, the forms guisu, ghisu and gìsu mean "gypsum" and come from the Catalan word guix, rather than from the Latin gypsum or the Greek gypsos. Rossoni specifies that the surname is typical of Sardinia, in particular of the Nuoro area, while the variant Guisu, very rare, is found in Sassari and its area.

V. Blunda, by contrast, presents it as a surname proper to Sicily, and attributes to it a Germanic root: it would derive from the personal name Wiso, a hypocoristic form built on the root wis —"wise, prudent, knowing"—, the same one that gave modern German weise and English wise. In ancient Germanic anthroponymy, this quality of practical wisdom was regarded as complementary to warrior valour, proper to the mature chief capable of considered deliberation.

The two proposals are incompatible as to geographical origin and etymon: Rossoni points to Sardinia and to Latin or Catalan bases, while Blunda goes back to Sicily and to the Germanic anthroponymic tradition. The surname therefore has multiple independent clusters of origin (ceppi) whose relation has not been established.