Abstract Nanoencapsulation is a valid alternative for the oral administration of peptide drugs and proteins, as nanoparticles protect them from proteolytic degradation in the gastrointestinal tract and promote the absorption of these macromolecules. The orofacial antinociceptive effect of frutalin (FTL), through the intraperitoneal route, has already been proven. This study aimed to develop, characterize, and evaluate the orofacial antinociceptive activity of an oral formulation containing FTL in acute and neuropathic preclinical tests. The analyzed sample did not show any cytotoxicity; 52.2% of the FTL was encapsulated, the size of the nanocapsules was less than 200 nm, the polydispersion was 0.361 and the zeta potential was - 5.87 millivolts. Nanoencapsulated FTL administered by oral route had an orofacial antinociceptive effect in acute and neuropathic rodent models. The antinociceptive effect of FTL was prevented by ruthenium red, but not by camphor. FTL reduced Trpv1 gene expression. FTL promotes orofacial antinociception probably due to the antagonism of TRPV1 channels and the nanoformulation represents an effective method of administering this protein orally.