Numerous natural phytochemicals such as resveratrol are acknowledged as potent botanical agents in regulating immune responses. However, it is less understood whether such immunomodulatory phytochemicals are appropriate for use as direct treatments in veterinary viral diseases. In the present study, we investigated the efficacy of resveratrol in suppressing vesicular stomatitis virus (VSV) infection. Outbreaks of VSV can cause massive economic loss in poultry and livestock husbandry farming, and VSV treatment is in need of therapeutic development. We utilized a recombinant VSV that expresses green fluorescent protein (GFP) to measure viral replication in cells treated with resveratrol. Our findings revealed that resveratrol treatment affords a protective effect, shown by increased viability and reduced viral replication, as indicated by a reduction in fluorescent signals. Additionally, we found that resveratrol inhibition of VSV infection occurs via suppression of the caspase cascade. Structural analysis also indicated that resveratrol potentially interacts with the active sites of caspase-3 and -7, facilitating antiviral activity. The potential effect of resveratrol on reducing VSV infection in vitro suggests that resveratrol should be further investigated as a potential veterinary therapeutic or prophylactic agent.