Background Alcoholic liver disease (ALD) is regarded as a global health problem with limited therapeutic options. Previous studies highlighted some anticancer, antiviral, and hepatoprotective activities of limonoids, but the effects of these compounds on ALD remain unknown. The present study aimed to evaluate the effect of some natural limonoids on ethanol-induced liver injury. Methods Thirty-five albino mice ( Mus musculus ) were administered with 40% ethanol in the presence or absence of the different limonoids [including three havanensin-type limonoids, TS1, TS3, Rubescin D isolated from an African medicinal plant, Trichilia rubescens Oliv. (Meliaceae), and one limonin], or silymarin at 50 mg/kg for 3 days. Thereafter, the effect of the most active compound was evaluated in a chronic model of ALD. For this purpose, 24 mice with each group consisting of six mice were administered orally with 40% ethanol and limonoid at different doses (50, 75, and 100 mg/kg) for 28 days. Finally, biochemical parameters such as alanine aminotransferase (ALT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), triglyceride (TG), and tumor necrosis factor α (TNF-α) levels were quantified in liver homogenates. Results All tested limonoids significantly (p < 0.01) reduced ALT levels relative to the negative control in the acute model. However, in comparison to other limonoids, limonin at 50 and 75 mg/kg significantly reduced TG, MDA, and TNF-α levels (1.8-fold); alleviated leukocyte infiltration in liver tissue; significantly increased the activity of SOD; and decreased those of CAT better than silymarin used as a positive control at 50 mg/kg. Conclusions These data suggest that limonin possesses protective effects on long-term alcohol poisoning partially due to antioxidant and anti-inflammatory mechanisms.