Introduction: In the sports scenario, cannabidiol (CBD) is a phytocannabinoid that has been accumulating important scientific evidence in various metabolic and metabolomic effects. Δ9 tetrahydrocannabinol (Δ9-THC) may be responsible for some adverse effects on sports performance and this makes cannabis unattractive for athletes. Extracellular vesicles (exosomes and microRNAs) induced by exercise emerged as potential mediators of tissue crosstalk. Objective: It was to carry out a systematic review study to highlight the main outcomes of cannabidiol in metabolic modulation and microRNA signaling in increasing sports performance. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from March to May 2023 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 127 articles were found. A total of 87 articles were evaluated in full and 62 were included and developed in this systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 5 studies with a high risk of bias and 11 studies that did not meet GRADE. It has been shown that cannabidiol exerts some physiological, biochemical, and psychological effects with the potential to benefit athletes. For example, there is preliminary supporting evidence for the anti-inflammatory, neuroprotective, analgesic, and anxiolytic actions of cannabidiol and the possibility that it may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, it is important to recognize that these findings are very preliminary, sometimes inconsistent, and largely derived from preclinical studies. These studies are limited in their generalizability to athletes and often administer high doses of cannabidiol. The central observation is that there is a lack of studies that directly investigate cannabidiol and sports performance. Furthermore, we identified a specific repertoire of microRNAs that are regulated by cannabinoids, at rest (vigilant), and in microglia activated by lipopolysaccharides. Modulated microRNAs and their target genes are controlled by TLR, Nrf2, and Notch cross-signaling and are involved in the immune response, cell cycle regulation, as well as cellular stress and redox homeostasis.