Background: Cocaine and methamphetamine (METH) are potent stimulant drugs that significantly affect the central nervous system (CNS) by increasing neurotransmitter activity, leading to heightened euphoria and increased addiction potential. In addition to their neurological effects, these stimulants disrupt the gut microbiome composition, resulting in dysbiosis that may further influence brain function and neurobiology. This systematic review examines the impact of cocaine and methamphetamine on the gut microbiome and neurobiology. The studies reviewed employed various bioinformatics and computational methods, to analyze microbiome data from animal models. By examining these connections, this review highlights the potential role of the gut-brain axis in shaping addiction pathways and offers insights into future therapeutic strategies aimed at microbiome modulation. Methods: We conducted a systematic review using databases such as PubMed, Google Scholar, Scopus, and Web of Science to identify studies published in recent years that investigated the effects of cocaine and methamphetamine on the gut microbiome and neurobiology. Our search focused on animal studies due to the limited availability of human research in this area. Results: Cocaine use reduced gut microbiota diversity in mice, decreasing the abundance of beneficial genera such as Mucispirillum and increasing the abundance of harmful taxa such as Barnesiella, leading to a proinflammatory gut environment. Methamphetamine (METH) use in rats increased microbial diversity but decreased beneficial bacteria such as Phascolarctobacterium, linking gut alterations to inflammation and mental health issues. Both substances disrupt the gut microbiota, impacting addictive behaviors through the microbiota‒gut‒brain axis. Conclusion : Cocaine and methamphetamine significantly alter the composition of the gut microbiota, which in turn affects neurobiology and contributes to neuroinflammation and mental health issues. These findings underscore the crucial role of the microbiota‒gut‒brain axis in addiction mechanisms and highlight potential therapeutic targets for substance use disorders. Further research is necessary to elucidate these relationships and their implications for treatment strategies.