Argulosis is a major problem that causes huge economic loss in aquaculture. In a microcosm, an infested condition was developed upon Labeo rohita with 100 ± 10 adult morphs of Argulus bengalensis per fish. Primary stress response and biochemical profiles of the host were evaluated to underscore the pathogenicity of the parasites. Significant alterations in biochemical parameters were monitored at four different post‐infestation time points: days 1, 3, 6 and 9. The overall increasing trends of both plasma cortisol and plasma epinephrine indicate parasite‐induced primary stress response among experimental fish. The study revealed a hyperglycaemic trend throughout the infestation period, which has been correlated with hypoxia‐associated glycogenolysis. Decreasing level of plasma cholesterol has also been correlated with the development of anaemia and subsequent hypoxia among the infested fish. Plasma protein of the experimental fish initially increases as an outcome of the immediate innate immune response against Argulus infestation, whereas the decrease in plasma protein at the later period of infestation results from less‐dietary protein intake due to loss of appetite, reduced digestibility and metabolic proteolysis. Plasma Na+ concentration showed an overall decreasing trend throughout the infestation period, which may be due to excess production of catecholamine under stress. Nonetheless, plasma K+ concentration showed an increasing trend up to day 6 of infestation, and thereafter the value declined to the control level. Plasma ionic imbalances reflect changes in cell permeability under tissue hypoxia and the wounds produced on the skin for intensive feeding activity of the parasites. Both serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase activities were significantly elevated throughout the infestation period, which indicates excess synthesis or release of those enzymes from the damaged cells of the tissues. Activities of some renal, hepatic and branchial antioxidant enzymes, viz., superoxide dismutase, catalase and glutathione‐S‐transferase, increased in the infested fish. The fact is explained as an effort of the fish for gaining adaptive adjustment to neutralize the oxidative stress generated under the parasitic stress. The overall experimental result points towards the generation of potential stress upon host fish by this branchiuran parasite. The biochemical alterations of the fish under argulosis are centred around the two stress‐sensitive hormones, cortisol and epinephrine. The outcome of the study will be the important physiological determinants in adopting a suitable control measure as well as assessing the nutritional value of the fish under diseased condition.