Lyssaviruses cause acute, progressive encephalitis in mammals. Current rabies vaccines offer protection against the lyssaviruses, with the notable exceptions of Mokola virus (MOKV), Lagos bat virus (LBV) and West Caucasian bat virus (WCBV). Here we describe the cross-protective and cross-reactive immune responses induced by experimental recombinant vaccinia viruses encoding the glycoprotein genes of rabies virus (RABV), MOKV and WCBV, either singly or in dual combinations. Constructs expressing a single glycoprotein gene protected mice against lethal intracranial challenge with homologous virus. Similarly, recombinants expressing glycoprotein genes from two different lyssaviruses offered mice protection against both homologous viruses. VNAb induced by vaccines that included a MOKV glycoprotein gene cross-neutralized LBV, but not WCBV. We concluded that a single recombinant poxvirus-vectored vaccine including MOKV and RABV glycoprotein genes, should be a major addition to available rabies biologics and should offer broad protection against all of the lyssaviruses, except WCBV.