Objective: To investigate the effects of sinomenine on brain edema and the expression of aquaporin 4 (AQP-4) and aquaporin 5 (AQP-5) in rats with acute brain injury. Methods: According to random number table method, rats were divided into sham operation group, model group, low-dose sinomenine group, high-dose sinomenine group, 20 in each group. In addition to the sham operation group, the rat brain injury model was established by Feeney free falling impact method. Rats in low and high dose of sinomenine group were given sinomenine 30, 60 mg/kg by intraperitoneal injection, and the sham operation group and model group were injected intraperitoneally with the same volume of normal saline, once per day for 7 days. Histopathological changes in each group were observed by HE staining and electron microscope. Western blot and RT-PCR were used to detect AQP-4 and AQP-5 protein and gene expression in brain tissue. Results: The pathological results showed that the nerve cells in the model group were loosely arranged, disordered in hierarchy, some cells appear to have degenerated. The degeneration and necrosis of nerve cells in the low and high dose sinomenine group were less than those in the model group. Compared to the model group, the expression of AQP-4 (0.74 ± 0.13, 0.49 ± 0.11 vs. 1.30 ± 0.21), AQP-5 (0.98 ± 0.07, 0.45 ± 0.10 vs. 1.47 ± 0.18) in the low dose and high dose sinomenine group significantly decreased (P<0.05). The expression of AQP-4 (1.48 ± 0.18, 1.26 ± 0.12 vs. 2.04 ± 0.14), AQP-5 (1.31 ± 0.17, 1.20 ± 0.11 vs. 1.87 ± 0.15) mRNA in the low dose and high dose sinomenine group significantly decreased (P<0.05). Conclusions Sinomenine could alleviate cerebral injury by lowering the expression of AQP-4 and AQP-5.