This study was aimed at analyzing the bioaccumulation of phenols, histopathological alterations, and oxidative stress biomarker response in Heterotis niloticus from Epe lagoon, Lagos, Nigeria. The study investigated the concentration of phenol in the intestine, liver and parasite of Heterotis niloticus fish in a Epe lagoon. Specimens of H. niloticus were freshly purchased randomly from the Olowu waterside market in Epe. The oxidative stress biomarker response was also carried out to examine the stress caused to Heterotis niloticus in Epe lagoon, on exposure to phenolic compounds. Also, physical and chemical parameters of the surface water where the fishes were collected were also analyzed. Most of the physicochemical parameter results showed no significant variations in relation to established limits, excluding Ph which was slightly acidic, and Dissolved Oxygen which exceeded the permissible limits. 2-Nitro-Phenol, 4-Chloro-3-methyl-Phenol, 2, 4, 6-Trichloro-Phenol and 4-Nitro-Phenol are the phenol compounds present in the intestine, 2-Nitro-Phenol, 2, 4, 6-Trichloro-Phenol and 4-Nitro-Phenol were found in the liver, while only 2-Nitro-Phenol and 4-Nitro-Phenol were found in the parasite of Heterotis niloticus in Epe lagoon, Lagos. The oxidative stress biomarker GPx was highest in the intestine, SOD was highest in the parasite, while MDA, GSH and CAT were significantly low in the intestine, liver and parasite of the fish. Significant histopathological alterations in the whole organisms were observed in the intestine of the fish samples. The pathological findings in the infected fish ranged from increase in the connective tissue of the submucosa, focal area of haemorrhagic lesion and loss of villous structure. The findings show how phenol pollution affects aquatic organisms and also reflects the poor health condition of the Epe lagoon, Lagos Nigeria.