Central post-stroke pain (CPSP) is a neuropathic pain syndrome that frequently occurs following cerebral stroke. The pathogenesis of CPSP is mainly due to thalamic injury caused by ischemia and hemorrhage. However, its underlying mechanism is far from clear. In the present study, a thalamic hemorrhage (TH) model was established in young male mice by microinjection of 0.075 U of type IV collagenase into the unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus. We found that TH led to microglial pannexin (Panx)-1, a large-pore ion channel, opening within the thalamus accompanied with thalamic tissue injury, pain sensitivities, and neurological deficit, which were significantly prevented by either intraperitoneal injection of the Panx1 blocker carbenoxolone or intracerebroventricular perfusion of the inhibitory mimetic peptide 10Panx. However, inhibition of Panx1 has no additive effect on pain sensitivities upon pharmacological depletion of microglia. Mechanistically, we found that carbenoxolone alleviated TH-induced proinflammatory factors transcription, neuronal apoptosis, and neurite disassembly within the thalamus. In summary, we conclude that blocking of microglial Panx1 channels alleviates CPSP and neurological deficit through, at least in part, reducing neural damage mediated by the inflammatory response of thalamic microglia after TH. Targeting Panx1 might be a potential strategy in the treatment of CPSP.