Mosquito-borne viruses such as Alphaviruses and Flaviviruses have been the cause of several outbreaks worldwide in the past 10 years. In these outbreaks, the risk to global public health was significant, as was seen with the recent Chikungunya and Zika virus epidemics. Chikungunya virus (CHIKV) is an alphavirus that causes severe arthritis, arthralgia and fever, and has been re-emerging worldwide since a large outbreak in the Indian Ocean in 2006. Musculoskeletal inflammation in CHIKV disease has been attributed to host innate immune responses, but the specific mechanisms remain to be elucidated. Cellular responses to pathogens and other cellular damage mechanisms have been shown to activate the inflammasome pathway, leading to subsequent release of pro-inflammatory cytokines. We found that the NLRP3 inflammasome was activated in CHIKV-infected patients suffering acute disease, with high serum levels of IL-18 and IL-1β, and this observation was replicated in a mouse model of CHIKV infection. Administration of a small-molecule NLRP3 inhibitor to CHIKV-infected mice led to reduced arthritic score, and modulated the pro-inflammatory cytokine expression profile in inflamed tissue. In addition, NLRP3 inhibition reduced osteoclastogenic bone loss and muscle inflammation in CHIKV-infected mice. Importantly, while similar results were observed in mice infected with Ross River virus, an Australian alphavirus, NLRP3 inhibition had no effect on a flavivirus model of West Nile virus encephalitis, indicating a virus- and tissue-specific mechanism by which NLRP3 drives viral inflammation. Our data shows that the NLRP3 inflammasome is a key driver of alphavirus-induced musculoskeletal inflammation, and that specific targeting of NLRP3 offers a viable therapeutic approach for acute CHIKV-induced inflammation.