The contamination of the aquatic ecosystem beyond tolerable limits may pose serious health challenges to its components. This study evaluated the toxic effects of a binary mixture of lead (Pb) and zinc (Zn) compounds on the activity of Na + /K + -ATPase in tissues of Clarias gariepinus in a controlled aquatic system. The study employed Box-Behnken Design (BBD) with 17 runs in which Pb and Zn concentrations were considered process variables in a time-dependent fashion. Metal exposure levels consisted of 0, 10 and 20% of 96 h-LC 50 of Pb (55.12 mg/L) and Zn (32.15 mg/L) for three weeks. Thereafter, membrane-bound Na + /K + -ATPase activity was assessed in gill, hepatic and renal tissues, and data generated from the BBD were used for the development of models. Three regression models were obtained, for gill, hepatic and renal Na + /K + -ATPase activities with exposure to metals differ significantly (p < 0.05) at R 2 > 90%, and no significant lack of fit (p > 0.05) was observed in each case. Congruent to the synergistic interactions observed between Pb and Zn in the study, the gill and hepatic Na + /K + -ATPase activities were significantly inhibited, whereas renal Na + /K + -ATPase activity was significantly stimulated (p < 0.05). The optimized models were considered reliable, as they were confirmed in the laboratory through accurate prediction of hepatic, renal and gill Na + /K + -ATPase activities with equivalences of 1.22 ± 0.17, 1.66 ± 0.07 and 3.50 ± 0.33 µmol p i /min/mg protein (p < 0.05) respectively. It is hereby concluded that the synergistic interaction between Pb and Zn truncated the physiological function of Na +/ K + -ATPase activity in the respective tissues except for renal tissue of exposed C. gariepinus. Keywords C. gariepinus • Lead • Na + /K + -ATPase activity • Toxic effects • Zinc * Augustine Apiamu