Brain injuries are serious health problems and require appropriate management strategies in the healing process. The purpose of this research was to determine the effect of minocycline and single N-Acetylcysteine compared to the administration of a combination of minocycline or NAC in reducing the expression of Aquaporin-4 (AQP-4) in the brains of experimental animals with brain injuries for seven days after brain injury. The experimental animals were wistar mice (n = 65) that were divided into 5 groups. 1) brain injury treatment and minocycline 45 mg/kg body weight orally (MN), 2) brain injury treatment and NAC 150 mg/kg intraperitoneal (NAC), 3) brain injury treatment and minocycline combination NAC (MCN), 4) brain injury treatment and positive control 0.9% saline 1cc intra peritoneal (PC), and 5) without treatment of brain injury and drug administration (NC). The subjects were observed on days 3, 5 and 7. The repeated measures ANOVA was applied to analyze the data with SPSS v.25. The combination of MN 13.5 mg and NAC 45 mg/kg body weight (4.62, 95% CI 3.40; 5.83 & 6.76, 95% CI 4.90; 8.61 p = 0.00) did not perform better than a single dose of each drug on Aquaporin-4. Moreover, the combination of NAC and Minocycline had no effect on Aquaporin-4 and the administration of a single drug minocycline was found to be better on the 3rd and 5th days, while the administration of NAC was better on the 7th day as shown by the decrease in Aquaporin-4 levels.