Mayaro virus (MAYV) is endemic in South American countries where it is responsible for sporadic outbreaks of acute febrile illness. The hallmark of MAYV infection is a highly debilitating and chronic arthralgia. Although MAYV emergence is a potential threat, there are no specific therapies or licensed vaccine. In this study, we developed a murine model of MAYV infection that emulates many of the most relevant clinical features of the infection in humans and tested a live-attenuated MAYV vaccine candidate (MAYV/IRES). Intraplantar inoculation of a WT strain of MAYV into immunocompetent mice induced persistent hypernociception, transient viral replication in target organs, systemic production of inflammatory cytokines, chemokines and specific humoral IgM and IgG responses. Inoculation of MAYV/IRES in BALB/c mice induced strong specific cellular and humoral responses. Moreover, MAYV/IRES vaccination of immunocompetent and interferon receptor-defective mice resulted in protection from disease induced by the virulent wt MAYV strain. Thus, this study describes a novel model of MAYV infection in immunocompetent mice and highlights the potential role of a live-attenuated MAYV vaccine candidate in host's protection from disease induced by a virulent MAYV strain.