Highlights Highly pathogenic avian influenza (HPAI) H5Nx viruses can cause neurological complications in many mammalian species, including humans.

Neurological disease induced by HPAI H5Nx viruses in mammals can manifest without clinical respiratory disease.

HPAI H5Nx viruses are more neuropathogenic than other influenza A viruses in mammals.

Severe neurological disease in mammals is related to the neuroinvasive and neurotropic potential of HPAI H5Nx viruses.

Cranial nerves, especially the olfactory nerve, are important routes of neuroinvasion for HPAI H5Nx viruses.

HPAI H5Nx viruses have a broad neurotropic potential and can efficiently infect and replicate in various CNS cell types.

Vaccination and/or antiviral therapy might in part prevent neuroinvasion and neurological disease following HPAI H5Nx virus infection, although comprehensive studies in this area are lacking.