NLRP3　inflammasome-mediated　pyroptosis　is　a　proinflammatory　programmed　cell　death　pathway,　which　plays　a　vital　role　in　functional　outcomes　after　stroke.　We　previously　described　the　beneficial　effects　of　curcumin　against　stroke-induced　neuronal　damage　through　modulating　microglial　polarization.　However,　the　impact　of　curcumin　on　microglial　pyroptosis　remains　unknown.　Here,　stroke　was　modeled　in　mice　by　middle　cerebral　artery　occlusion　(MCAO)　for　60　minutes　and　treated　with　curcumin　(150　mg/kg)　intraperitoneally　immediately　after　reperfusion,　followed　by　daily　administrations　for　7　days.　Curcumin　ameliorated　white　matter　(WM)　lesions　and　brain　tissue　loss　21　days　poststroke　and　improved　sensorimotor　function　3,　10,　and　21　days　after　stroke.　Furthermore,　curcumin　significantly　reduced　the　number　of　gasdermin　D+　(GSDMD+)　Iba1+　and　caspase-1+Iba1+　microglia/macrophage　21　days　after　stroke.　In　vitro,　lipopolysaccharide　(LPS)　with　ATP　treatment　was　used　to　induce　pyroptosis　in　primary　microglia.　Western　blot　revealed　a　decrease　in　pyroptosis-related　proteins,　e.g.,　GSDMD-N,　cleaved　caspase-1,　NLRP3,　IL-1β,　and　IL-18,　following　in　vitro　or　in　vivo　curcumin　treatment.　Mechanistically,　both　in　vivo　and　in　vitro　studies　confirmed　that　curcumin　inhibited　the　activation　of　the　NF-κB　pathway.　NLRP3　knocked　down　by　siRNA　transfection　markedly　increased　the　inhibitory　effects　of　curcumin　on　microglial　pyroptosis　and　proinflammatory　responses,　both　in　vitro　and　in　vivo.　Furthermore,　stereotaxic　microinjection　of　AAV-based　NLRP3　shRNA　significantly　improved　sensorimotor　function　and　reduced　WM　lesion　following　curcumin　treatment　in　MCAO　mice.　Our　study　suggested　that　curcumin　reduced　stroke-induced　WM　damage,　improved　functional　outcomes,　and　attenuated　microglial　pyroptosis,　at　least　partially,　through　suppression　of　the　NF-κB/NLRP3　signaling　pathway,　further　supporting　curcumin　as　a　potential　therapeutic　drug　for　stroke.　©　2021　Yuanyuan　Ran　et　al.