Omega-3 fatty acids (-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with -3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1 secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein -arrestin-2 were shown to be involved in inflammasome inhibition induced by -3 FAs. Importantly, -3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which -3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of -3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases.