MCC950 is a specific nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome inhibitor that has neuroprotective properties in nervous system disorders. In this study, we investigated its cerebroprotective mechanism in sepsis-associated encephalopathy. We randomly divided 104 Sprague–Dawley rats into sham, sepsis-associated encephalopathy, and sepsis-associated encephalopathy+MCC950 groups. Hematoxylin–eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were employed to observe pathological changes in brain tissue and detect neuronal apoptosis, respectively. Western blotting was employed to detect the expression and intensity of apoptosis-related spot-like proteins and inflammatory factors. Compared to the sham group, all other groups exhibited significant increases in serum tumor necrosis factor alpha, interleukin-1β, interleukin-18, neuron-specific enolase, and S100β (P < 0.05) levels. The apoptosis rate of hippocampus in the sepsis-associated encephalopathy+MCC950 group was significantly lower than that in the sepsis-associated encephalopathy group at 48h and 72h (P < 0.05). The severity of hippocampal tissue lesions in the sepsis-associated encephalopathy+MCC950 group was reduced at 24 h, 48 h, and 72 h compared to the sepsis-associated encephalopathy group, but not at 6 h. Compared to the sepsis-associated encephalopathy group, the sepsis-associated encephalopathy+MCC950 group exhibited significant differences in the level and intensity of protein expression in rat hippocampal tissue at various time points (P < 0.05). Thus, MCC950 exerted cerebroprotective and ameliorative effects in sepsis-associated encephalopathy rats by inhibiting inflammatory responses and pyroptosis mediated by the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome.