In this study, we have investigated biotransformation and oxidative stress responses in relation to tissue contaminant burden in the African sharptooth catfish (Clarias gariepinus) exposed to simulated leachate from a solid waste dumpsite in Calabar, Nigeria. Fish were exposed to simulated leachate, diluted to 0:0 (negative control), 1:10, 1:50, 1:100 and phenanthrene (a PAH: 50 μg/L used as a positive control) for 3, 7 and 14 days. Hepatic transcripts for cat, sod1, gpx1, gr, gst, cyp1a, cyp2d3, and cyp27 were analyzed by real-time PCR, while enzymatic assays for ethoxyresorufin O-deethylase (EROD), buthoxyresorufin O-deethylase (BROD), methoxyresorufin O-deethylase (MROD), pentoxyresorufin O-deethylase (PROD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), uridine diphospho-glucuronosyltransferase (UDPGT) and lipid peroxidase (LPO) were measured using standard methods. In addition, protein expression for CYP1A, CYP3A and metallotheionin (MT) were measured by immunoblotting. Fish muscle samples were analyzed for selected group of contaminants after 14 days exposure showing significantly high uptake of heavy metals (Cd, Hg and Pb), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), chlorophenols, organochlorine (OC) and organophosphate pesticides in exposed fish. We observed significant concentration- and time-specific increases in biotransformation and oxidative stress responses at transcript and functional (enzyme and protein) levels, that paralleled tissue contaminants bioaccumulation patterns, after exposure to the simulated leachates. Our results highlighted the potential environmental, wildlife and public health consequences from improper solid waste disposal. In addition, it also provides a scientific basis for local sensitization and inform legislative decisions and policy formulation towards sustainable environmental management of solid wastes in Nigeria and other developing countries.