In most cases the disease is transmitted via the bite of rabid animals which shed infectious virus with their saliva. The virus enters the body through transdermal inoculation (i.e. wounds) or direct contact of infectious material (i.e. saliva, cerebrospinal liquid, nerve tissue) to mucous membranes or skin lesions. The virus cannot penetrate intact skin.

After entry the virus binds to cell receptors. Viruses may replicate within striated muscle cells ore directly infect nerve cells.

The virus then travels via retrograde axoplasmatic transport mechanisms to the central nervous system. Both motor and sensory fibres may be involved depending on the animal infected. The incubation period varies from 2 weeks to 6 years (average 2–3 months) depending on the amount of virus in the saliva, the site of inoculation and the virus strain.

Once it has reached the CNS, rapid virus replication takes place, causing pathologic effects on nerve cell physiology. The virus then moves from the CNS via anterograde axoplasmic flow within peripheral nerves, leading to infection of some of the adjacent non-nervous tissues, for example, secretory tissues of salivary glands. The virus is widely disseminated throughout the body at the time of clinical onset. With shedding of infectious virus in saliva the infection cycle of rabies is completed.