Ketone body β-hydroxybutyrate (BHB) suppresses the NLRP3 inflammasome-mediated inflammatory response. BHB, but not acetoacetate or short-chain fatty acids like butyrate and acetate, inhibits NLRP3 inflammasome activation in response to various activators without affecting other inflammasomes such as NLRC4, AIM2, or the non-canonical caspase-11 inflammasome. Mechanistically, BHB prevents K+ efflux and reduces ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are independent of chirality, AMPK, reactive oxygen species (ROS), autophagy, or glycolytic inhibition. BHB blocks NLRP3 inflammasome activation without undergoing oxidation in the TCA cycle, independently of UCP2, Sirt2, and Gpr109a. BHB reduces NLRP3-mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), and urate crystal-induced body cavity inflammation. These findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases. The NLRP3 inflammasome controls caspase-1 activation and the release of pro-inflammatory cytokines IL-1β and IL-18 in macrophages. It is an important innate immune sensor that can be activated by various damage-associated molecular patterns (DAMPs). Ablation of NLRP3 attenuates several chronic diseases. Although immune-metabolic interactions via inhibition of glycolysis dampen pro-inflammatory responses, it is not known whether alternate metabolic fuels such as ketones impact the innate immune response. Ketone bodies BHB and AcAc are produced in the liver and serve as alternative energy sources for the brain, heart, and skeletal muscle during nutrient deprivation. BHB levels increase during fasting and low-carbohydrate diets. BHB inhibits NLRP3 inflammasome activation in response to various activators, including ATP, MSU crystals, and particulate matter. BHB does not affect other inflammasomes. BHB inhibits NLRP3 inflammasome activation independently of Gpr109a and starvation-regulated mechanisms. BHB inhibits NLRP3 inflammasome activation by preventing K+ efflux and reducing ASC oligomerization and speck formation.Ketone body β-hydroxybutyrate (BHB) suppresses the NLRP3 inflammasome-mediated inflammatory response. BHB, but not acetoacetate or short-chain fatty acids like butyrate and acetate, inhibits NLRP3 inflammasome activation in response to various activators without affecting other inflammasomes such as NLRC4, AIM2, or the non-canonical caspase-11 inflammasome. Mechanistically, BHB prevents K+ efflux and reduces ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are independent of chirality, AMPK, reactive oxygen species (ROS), autophagy, or glycolytic inhibition. BHB blocks NLRP3 inflammasome activation without undergoing oxidation in the TCA cycle, independently of UCP2, Sirt2, and Gpr109a. BHB reduces NLRP3-mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), and urate crystal-induced body cavity inflammation. These findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases. The NLRP3 inflammasome controls caspase-1 activation and the release of pro-inflammatory cytokines IL-1β and IL-18 in macrophages. It is an important innate immune sensor that can be activated by various damage-associated molecular patterns (DAMPs). Ablation of NLRP3 attenuates several chronic diseases. Although immune-metabolic interactions via inhibition of glycolysis dampen pro-inflammatory responses, it is not known whether alternate metabolic fuels such as ketones impact the innate immune response. Ketone bodies BHB and AcAc are produced in the liver and serve as alternative energy sources for the brain, heart, and skeletal muscle during nutrient deprivation. BHB levels increase during fasting and low-carbohydrate diets. BHB inhibits NLRP3 inflammasome activation in response to various activators, including ATP, MSU crystals, and particulate matter. BHB does not affect other inflammasomes. BHB inhibits NLRP3 inflammasome activation independently of Gpr109a and starvation-regulated mechanisms. BHB inhibits NLRP3 inflammasome activation by preventing K+ efflux and reducing ASC oligomerization and speck formation.