Copper II-Albumin complex (Cu-II-Albumin complex) is a novel therapeutic target that has been used as anti-inflammatory, antioxidant, and anti-gastrointestinal toxicity. In this study, 40 rats were divided into four groups, normal control (NC), aflatoxicosed group (AF) that received Aflatoxin B1 (AFB1) (50 μg/kg of the AFB1 daily for 3 weeks), AFB1-Cu-II-Albumin prophylactic group (AF/CUC-P) that subjected to intermittent treatment between AFB1 and Cu-II-Albumin complex (0.05 g/kg Cu-II-Albumin complex) day after day for 3 weeks and AFB1-Cu-II-albumin treatment group (AF/CUCT) that received AFB1 for 3 weeks and Cu-II-albumin complex for another 3 weeks. The hepatocellular protective effect of the Cu-II-albumin complex was assessed by evaluating the liver functions markers, hepatic histopathology, reactive oxygen species (ROS) levels (Nitric Oxide (NO) and malondialdehyde (MDA)), apoptotic genes (caspase-3 and tumor necrosis factor receptor 1 [TNF-R1]) expressions, and serological and molecular biomarkers of hepatocellular carcinoma (histamine and GlucoseRegulated Protein 78 [GRP78], respectively). Our finding showed that Cu-II-Albumin Complex administration had restored liver function, oxidative stress levels, enhanced liver tissue recovery, and reduced the expression of the apoptotic genes of the aflatoxicosed rats. In conclusion, the current study results demonstrated the protective effect of Cu-II-albumin complex against AFB1-induced hepatocellular toxicity