Abstract The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well‐known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA‐approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide‐induced systemic inflammation and Parkinson's disease‐like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3‐driven diseases and migth expand its clinical use considerably. Synopsis image Mefloquine is a highly selective and potent NLRP3 inhibitor. Mefloquine directly binds to the NACHT and LRR domains of NLRP3, impairs inflammasome assembly and reduces NLRP3‐dependent systemic inflammation and neural injury in mice. By screening a panel of FDA‐approved drugs, mefloquine is identified as a potent and specific NLRP3 inhibitor. Mefloquine directly binds to NLRP3 and inhibits inflammasome activation. Mefloquine suppresses LPS‐induced NLRP3‐driven systemic inflammation and neural injury in mice.