Mosquitoes cause more human suffering that any other organism, with over a million people dying each year from mosquito-borne diseases. The increasing global distribution of arthropod vectors means that many pathogens, including alphaviruses (eg chikungunya) and flaviviruses (eg dengue and Zika), are now invading new areas of the world. Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease with crippling pain and joint arthritis. Currently there is no licenced specific treatment for any alphavirus disease and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Drug ‘repurposing’ refers to studying a small molecule previously approved to treat one disease or condition to see if it is safe and effective for treating other diseases. Recently there has been an increase in the push towards research into drug repurposing. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects and is currently licensed under the name Elmiron® for the treatment of cystitis in many parts of the world including Australia and the USA. Our findings show RRV infection damages the articular cartilage including a loss of proteoglycans within joint, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. Reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex analysis we show PPS treatment significantly increased the anti-inflammatory cytokine interleukin-10 and reduced pro-inflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. Given the results of this study, the positive and extensive long-term human safety data on PPS, and its availability as an approved drug by a number of regulatory authorities globally, we propose PPS is a promising and available drug-repurposing candidate for the treatment of alphavirus-induced arthritis.