Histamine receptors play pivotal roles in various physiological functions, ranging from allergic responses to memory and sleep regulation, making them important drug targets. While second-generation antihistamines have been successfully used in rodents and humans, investigating their effects in non-traditional animal models enhances our understanding and aids the development of novel drug candidates. In this study, we examined the impact of the first-generation drug chloropyramine and the second-generation drugs loratadine and cetirizine, at concentrations of 1, 5, and 10 mg/L, on adult zebrafish b-ehavior using the novel tank test. All three drugs significantly altered fish locomotor a-ctivity, decreasing distance traveled and average velocity while increasing low acceleration frequency. Chloropyramine at 5 and 10 mg/L and loratadine at 1, 5, and 10 mg/L significantly reduced top entries compared to the control. Additionally, 5 mg/L chloropyramine increased the total duration of top entries, whereas loratadine at 10 mg/L r-educed this behavior compared to controls. Overall, chloropyramine and loratadine e-xhibited a sedative effect typical of antihistamines, while cetirizine solely reduced locomotor activity without affecting other patterns of fish behavior. Thus, cetirizine demonstrated the least impact on the central nervous system among the studied drugs, making it the optimal and safest choice among antihistamines.