Recent European guidelines facilitate the use of emergency vaccines during outbreaks of foot‐and‐mouth disease. Antiviral drugs could be used as a complementary measure. This study aimed at developing a small animal model to assess the in vivo activity of early antiviral lead molecules with anti‐foot‐and‐mouth disease virus (FMDV) activity in vitro. In a first attempt, several FMDV strains were titrated in Balb/c mice. Inoculations with O1 Manisa or C1 Noville did not induce clinical disease, whereas Asia1 Shamir induced death too rapidly [i.e. within 4 days post‐inoculation (dpi)]. Therefore, we switched to severe combined immunodeficient mice which are frequently used as a model for viral infections and experimental therapeutics. Strain O1 Manisa did not induce clinical disease, but titrations with A22 Iraq, C1 Noville or Asia1 Shamir resulted in virus‐induced morbidity (including respiratory problems and weight loss) with subsequent mortality. Inoculations with strain A22 Iraq resulted in a reproducible mean time of death of 6 dpi (this was shorter for the other strains). In this newly developed rodent model, strain A22 Iraq seems the most suited to assess the in vivo anti‐FMDV activity of selective inhibitors of FMDV.