Although most countries banned manufacturing of polychlorinated biphenyls (PCBs) over 40 years ago, PCBs remain a global concern for wildlife and human health due to high bioaccumulation and biopersistance. PCB uptake mechanisms have been well studied in many taxa; however, less is known about depuration rates and how post-exposure diet can influence PCB concentrations and immune response in fish and wildlife populations. In a controlled laboratory environment, we investigated the influence of subchronic dietary exposure to two PCB Aroclors and food deprivation on tissue-specific concentrations of total PCBs and PCB homologs and innate immune function in channel catfish (Ictalurus punctatus). Overall, we found that the concentration of total PCBs and PCB homologs measured in whole body, fillet, and liver tissues declined more slowly in food deprived fish, with slowest depuration observed in the liver. Additionally, fish that were exposed to PCBs had lower plasma cortisol concentrations, reduced phagocytic oxidative burst activity, and lower cytotoxic activity, suggesting that PCBs can influence stress and immune responses. However, for most measures of immune function, the effects of food deprivation had a larger effect on immune response than did PCB exposure. Taken together, these results suggest that short-term dietary exposure to PCBs can increase toxicity of consumable fish tissues for several weeks, and that PCB mixtures modulate immune and stress responses via multiple pathways. These results may inform development of human consumption advisories and can help predict and understand the influence of PCBs on fish health.