Histamine receptors play a pivotal role in various physiological functions (ranging from allergic responses to memory and sleep regulation), hence representing important drug targets. While second-generation antihistamines have successfully been used in rodents and humans, testing their effects in non-traditional animal models furthers our understanding of their physiological activity and facilitates the development of novel drug candidates. Here, we examined the effects of the first-generation antihistaminic drug chloropyramine and the second-generation drugs loratadine and cetirizine, at concentrations of 1, 5, and 10 mg/L, on adult zebrafish behavior in the novel tank test. All three drugs significantly altered zebrafish locomotor activity, decreasing the distance traveled and average velocity, as well as increasing low acceleration frequency. Chloropyramine (5 and 10 mg/L) and loratadine (1, 5, and 10 mg/L) also significantly reduced top entries compared to the control. Additionally, chloropyramine (5 mg/L) increased the total duration of top entries, whereas loratadine (10 mg/L) reduced this behavior compared to controls. Overall, chloropyramine and loratadine exhibited a sedative effect typical of antihistamines, whereas cetirizine solely reduced locomotor activity without affecting other patterns of fish behavior. Thus, cetirizine demonstrated the least side effects on the central nervous system among the studied drugs, making it the optimal and safest choice among antihistamines.