This study evaluated the physiological effects of sublethal concentrations of Cd2+ and Pb2+, both individually and in combination, on Channa marulius, an important species in local fisheries. A total of 160 fish were divided into four groups (control, Cd2+-treated, Pb2+-treated, and Cd2+ + Pb2+ treated) and exposed to 30% of the 96-hour LC50 values for CdCl2 (22.71 mg/L), PbCl2 (16.02 mg/L), and their combination for 40 days. Results showed significantly (P < 0.05) higher Cd2+ and Pb2+ concentrations in the tissues of exposed groups compared to controls, with the highest accumulation in the kidney, followed by gills and intestines. Enzyme activities of catalase (CAT) and superoxide dismutase (SOD) were significantly reduced, especially in the combined exposure group. Additionally, red blood cells, hemoglobin, and total protein levels decreased, while cortisol and glucose levels increased, indicating stress. Acetylcholinesterase (AChE) activity in the gill and liver was also significantly inhibited in the combined exposure group. These findings highlight the risks posed by combined heavy metal exposure to fish physiology, underscoring potential threats to fish health and local fisheries.