OBJECTIVES: Endosulfan is a broad-spectrum organochlorine insecticide that has been commercially in use for decades to control insect pests and has been found to pollute the aquatic environment. The current study was carried out to investigate the toxic effects of endosulfan, an organochlorine pesticide, on Nile tilapia (Oreochromis niloticus), a freshwater fish, and the alleviating effects of lycopene on the induced toxicity. METHODS: Four treatment groups of fish were investigated (3 replicates of 15 fish for each group): (1) a control group, (2) a group exposed to endosulfan, (3) a group that was fed on a basal diet supplemented with lycopene, and (4) a group that was fed on a basal diet supplemented with lycopene and exposed to endosulfan. The experiment was carried out over a 4-week period. RESULTS: Endosulfan negatively affected liver function, including liver enzymes and plasma proteins. Endosulfan affected blood parameters of fish and reduced the counts of red blood cells (RBCs) and white blood cells (WBCs), as well as affected immunological parameters. Endosulfan caused oxidative stress, as it decreased the values of antioxidants catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione (GSH), and increased the level of lipid peroxide malondialdehyde (MDA). Additionally, endosulfan increased cytochrome P450 (CYP450) levels, while it decreased glutathione S-transferase (GST) mRNA transcript levels and distorted the normal histological structure of the liver, gills, and spleen of affected fish. Conversely, lycopene partially restored the aforementioned parameters when administered concomitantly with endosulfan. CONCLUSION: The results showed the beneficial effects of supplementing fish diets with lycopene as a natural antioxidant for ameliorating the toxicity caused by endosulfan.