Environmental contamination by agricultural chemicals, particularly herbicides, poses a significant threat to aquatic ecosystems and their inhabitants, including fish. This study aimed to evaluate the acute histological and behavioral alterations induced by exposure to a pretilachlor + pyribenzoxim herbicide mixture in Clarias gariepinus juveniles. Two hundred and fifty healthy C. gariepinus juveniles were acclimatized for two weeks. Batches of 10 fish per tank were randomly distributed into 18 experimental tanks. Following range-finding tests, a definitive acute toxicity test was conducted over 96 hours using various concentrations (0.40, 0.425, 0.45, 0.475, and 0.5 ml) of the herbicide. Throughout the experiment, water quality parameters, behavioral patterns, and mortality were meticulously monitored. Post-exposure, samples were collected for comprehensive histological analysis. Behavioral observations revealed significant stress indicators, including loss of reflex, air gulping, erratic swimming, barbell deformation, and molting. Histological examination of the gills showed infiltration of the mucous membrane of the secondary lamellae, which were also overlaid with detritus. In the kidneys, mild degeneration of the renal tubules accompanied by diffuse cellular infiltration was evident. Furthermore, the epidermis of the skin appeared detached from the underlying dermis. These pronounced histological and behavioral changes underscore the acute toxic effects of pretilachlor + pyribenzoxim on C. gariepinus. The study suggests that histological analysis is a highly useful method for assessing the acute impacts of herbicides on cultured fish. Consequently, the potential toxic effects of pretilachlor + pyribenzoxim must be carefully considered during its application near aquatic environments to mitigate ecological harm.