High-intensity interval training (HIIT) significantly reduced hippocampal necroptosis in T2DM mice by decreasing LDH release (p < 0.0001), PI-positive cells (p < 0.05), and RIPK1/RIPK3/MLKL protein levels (p < 0.05). HIIT also suppressed NLRP3 inflammasome activation and pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and iNOS expression (p < 0.05), effectively mitigating inflammation and protecting hippocampal neurons. The gene discussed is MLKL; the disease is type 2 diabetes mellitus.