Objective To investigate the neuroprotective effect of tongxinluo capsule on cognitive impairment of rats exposed to acute hypobaric hypoxia and its related mechanism. Methods Sixty-four male Sprague-Dawley rats were randomly divided into four groups: the control group, tongxinluo group ( TXL group), hypobaric hypoxia group ( HH group), and tongxinluo + hypobaric hypoxia group ( TXL + HH group). All rats were trained in a Morris water maze (MWM) for 5 days prior to hypobaric hypoxia exposure. They were then exposed to hypobaric hypoxia for 7 days. After 7 days, the rats’ cognitive function was evaluated by open field and MWM tests. The hippocampi were then extracted for molecular biological examination. Morphological changes were observed by pathological staining. The expressions of TLR-4, MyD88, IκBα, NF-κB p65, and AQP4 in the hippocampus were detected by Western blot. Results In the behavioral experiment, no significant difference in the open field test was observed among the four groups (P > 0. 05). Likewise, in the training part of the MWM tests, no significant difference in the escape latency was found among the four groups (P> 0. 05). However, in the probe trials, the residence time in the targeted quadrant and the crossing time to the original platform were significantly shorter in the rats exposed to hypobaric hypoxia than in the control group ( P< 0. 05). Tongxinluo treatment significantly attenuated hypobaric hypoxia-induced cognitive impairment ( P< 0. 05 ). Next, measurement of inflammatory markers showed that the serum and hippocampal IL-1β, TNF-α, and IL-6 levels as well as the hippocampal TLR-4, MyD88, and NF-κB p65 protein levels were all significantly higher in the HH group than in the control group (P< 0. 05). The levels of these inflammatory proteins decreased after TXL intervention ( P< 0. 05). Finally, examination of hippocampal tissue damage revealed that hypobaric hypoxia increased the brain water content, with increased AQP4 and MMP-9 expression in the hippocampus (P< 0. 05). The cells in the hippocampus were disordered with obvious swelling and blurred boundaries. However, after TXL intervention, the brain water content and AQP4 and MMP-9 expression were significantly reduced (P< 0. 05). Conclusion Acute hypobaric hypoxia exposure can lead to cognitive impairment and brain edema by activating the TLR-4/ MyD88 / NF-κB pathway. Tongxinluo intervention may improve cognitive impairment and brain edema by inhibiting the TLR-4/ MyD88 / NF-κB signaling pathway.