Drug abuse and brain disorders related to drug comsumption are public health problems with harmful individual and social consequences. The identification of therapeutic targets and precise pharmacological treatments to these neuropsychiatric conditions associated with drug abuse are urgently needed. Understanding the link between neurobiological mechanisms and behavior is a key aspect of elucidating drug abuse-related targets. Due to various molecular, biochemical, pharmacological, and physiological features, the zebrafish (Danio rerio) has been considered a suitable vertebrate for modeling complex processes involved in drug abuse responses. In this review, we discuss how the zebrafish has been successfully used for modeling neurobehavioral phenotypes related to drug abuse and review the effects of opioids, cannabinoids, alcohol, nicotine, and psychedelic drugs on the central nervous system (CNS). Moreover, we summarize recent advances in zebrafish-based studies and outline potential advantages and limitations of the existing zebrafish models to explore the neurochemical bases of drug abuse and addiction. Finally, we discuss how the use of zebrafish models may present fruitful approaches to provide valuable clinically translatable data.