Background: Alcohol is a major contributor of chronic liver disease worldwide. Medical treatment for alcoholic liver disease (ALD) is limited. Due to the roles of oxidative stress in the development of ALD, genistein, a natural antioxidant, might be beneficial in alleviating alcohol-induced liver injury. Materials and Methods: Eighteen male Sprague–Dawley® rats were divided into three groups (n = 6 each). Control group received distilled water, while alcohol group received 50% alcohol (8 g/kg body weight [BW] per day), and genistein group received genistein (16 mg/kg BW per day) dissolved in 50% alcohol (8 g/kg BW per day) for 4 weeks. At the end of the study, liver tissue was obtained for histopathology and immunohistochemistry for interleukin-18 (IL-18), hepatic malondialdehyde (MDA), and glutathione (GSH) measurement. Serum samples were analyzed for alanine transaminase (ALT) and tumor necrosis factor-α (TNF-α). Results: Alcohol-fed rats gained significantly less weight than control and genistein ones (48.83 ± 14.59, 142.83 ± 10.06 vs. 69.17 ± 7.33 g, respectively, P < 0.01). Serum ALT levels were also significantly lower in genistein group than in alcohol group (32.43 ± 12.90 vs. 120.30 ± 75.30; P < 0.05). Hepatic MDA levels were higher in alcohol group (0.13 ± 0.02 nmol/mg protein), while the levels were comparable between genistein (0.09 ± 0.02 nmol/mg protein) and control groups (0.1 ± 0.01 nmol/mg protein). There was a trend toward a decrease in GSH levels in alcohol-fed rats as compared to control ones. On the contrary, GSH levels were significantly increased in GSH-treated rats. Markers of inflammatory responses, such as IL-18 and TNF-α, were higher in alcohol group and declined toward the control group with genistein administration. Conclusion: Alcohol-induced hepatic cell damages through oxidative stress and inflammatory responses. Genistein could alleviate alcohol-induced liver injury through its antioxidant and anti-inflammatory properties.