The use of psychotropic drugs in clinical and translational brain research continues to grow, and the need for novel experimental models and screens is becoming widely recognized. Mounting evidence supports the utility of zebrafish (Danio rerio) for studying various pharmacological manipulations, as an alternative model complementing the existing rodent paradigms in this field. Here, we explore the effects of acute 20-min exposure to two commonly abused psychotropic compounds, Δ⁹-tetrahydrocannabinol (THC) and heroin, on adult zebrafish behavior in the novel tank test. Overall, THC administration (30 and 50 mg/L) produces an anxiogenic-like reduction of top swimming, paralleled with a slower, continuous bottom swimming. In contrast, heroin exposure (15 and 25 mg/L) evoked a hyperlocomotor response (with rapid bouts of bottom swimming and frequent 'bouncing' motions) without altering anxiety-sensitive top/bottom endpoints. The behavioral effects of these two compounds in zebrafish seem to parallel the respective rodent and human findings. Collectively, this emphasizes the growing significance of novel emerging aquatic models in translational drug abuse research and small molecule screening.