Highly pathogenic viruses in the Filoviridae family are causative agents of filovirus disease (FVD). Ebola virus (EBOV) is one such member and, of all filoviruses, represents the largest threat to global public health. The study of FVD has been hampered by the lack of tools to study filovirus infection outside maximum containment laboratories. Recombinant vesicular stomatitis virus (VSV) lacking its native glycoprotein and expressing a filovirus glycoprotein (VSV-filo GP) has improved our understanding of GP-mediated host–cell interactions as well as adaptive and humoral immune responses in in vitro and in vivo studies. Furthermore, mouse models suitable for these studies are readily available. Here, we describe multiple injection routes for investigating filovirus GP-mediated infection and pathogenesis using VSV-filo GP and interferon α/β receptor-deficient (Ifnar−/−) mice as models. These tools can be safely used outside maximum containment laboratories, are cost effective, and easy to manipulate.