To investigate whether hypertonic ice saline (HIS) treatment can inhibit penumbra brain edema formation and pyroptosis in rats with traumatic brain injury (TBI) by regulating the expression of aquaporin 4 (AQP4) and NLRP3 inflammasome, and to explore the molecular mechanism involving the regulation of the HMGB1/NF-κ B signaling pathway. Methods: Sixty Sprague-Dawley rats were randomly divided into three groups: sham, TBI control, and HIS , with 20 rats in each group. The TBI model was constructed using a modified Feeney's free-fall method, while the sham group underwent the same procedure without the impact. Postoperatively, the control group received normal saline treatment, and the HIS group received HIS treatment. The Morris water maze test was used to assess the cognitive ability of the rats. Brain edema was measured by determining the water content of brain tissue. Western blot was used to detect the expression of AQP4, NLRP3, pyroptosis-related proteins (Caspase-1, GSDMD), and HMGB1/NF-κB signaling pathway-related proteins (HMGB1, NF-κB, p-IκBα). Real-time quantitative PCR was used to measure the levels of AQP4 and the inflammatory cytokines IL-1β and TNF-α. Results: The water maze test results showed that, compared with the control group, the escape latency of rats in the HIS group was shortened (P<0.05) and the number of times they passed through the original platform quadrant increased (P<0.05). Western blot results showed that, compared with the sham group, AQP4 expression levels in both the control and HIS groups were increased (P<0.05). However, compared with the control group, AQP4 expression in the HIS group was significantly down-regulated (P<0.05). Additionally, compared with the control group, the expressions of pyroptosis-related proteins NLRP3, Caspase-1 and GSDMD were down-regulated in the HIS group. Furthermore, compared with the sham group, the levels of inflammatory factors IL-1 β and TNF-α were significantly up-regulated in both the control and HIS groups (P<0.05), while the levels of these inflammatory factors were significantly down-regulated in the HIS group compared with the control group (P<0.05). Western blot results also showed that HIS inhibited the activation of the HMGB1/NF-κ B signaling pathway. Conclusion: TBI can induce an increase in penumbra inflammation, brain edema and up-regulation of AQP4 expression. HIS treatment can significantly alleviate the inflammation and brain edema of the penumbra and reduce the expression of AQP4 after TBI in rats. The regulatory mechanism involves inhibiting the expression of pyroptosis-related proteins and blocking the activation of the HMGB1/NF-κB signaling pathway.