ABSTRACT The toxic effects of 2, 4-dichlorophenol (2, 4-DCP) on aquatic organisms are well-established; however, the details regarding the mechanisms underlying the toxicity, especially immunotoxicity are poorly understood. Consequently, the aim of this study was to investigate the histopathologic, oxidative stress and immunotoxic effects attributed to exposure to sublethal concentrations of 2,4-DCP in the African catfish, Clarias gariepinus. Juvenile C. gariepinus were exposed to 0.4, 0.8, or 1.6 mg/L 2, 4-DCP for 28 days after which blood and head kidney were extracted for the determination of various nonspecific innate immune parameters while the liver was excised for histopathology examination and measurement of oxidative stress biomarkers. Control fish were maintained in water spiked 10 µL/L ethanol, representing the solvent control. A significant increase was noted in the activities of lactate dehydrogenase and superoxide dismutase as well as in levels of lipid peroxidation and DNA fragmentation in a dose-dependent manner, with higher adverse effects observed at the highest concentration tested (1.6 mg/L). The total white blood cells (WBC) count was significantly elevated in fish exposed to 2,4-DCP compared to control. Myeloperoxidase content was decreased significantly in fish exposed to 2,4-DCP especially at the highest concentration (1.6 mg/L) compared to controls. The respiratory burst activity did not differ markedly amongst groups. Histopathological lesions noted included edema, leucocyte infiltration, and depletion of hemopoietic tissue in the head kidney of exposed fish. There was significant upregulation in the mRNA expression of tumor necrosis factor (TNF-α) and heat shock protein 70 (HSP 70) but downregulation of major histocompatibility complex 2 (MHC 2) in exposed fish. Data demonstrated that exposure to 2,4-DCP resulted in histopathological lesions, oxidative stress, and compromised immune system in C. gariepinus.