Cutaneous melanoma, a lethal neoplasm originating from epidermal melanocytes, stands out for its resistance to conventional therapies and high metastatic rate. Given the urgent need for new therapeutic approaches, this study focuses on the antitumor potential of natural compounds derived from plants, recognized as primary sources of antineoplastic chemotherapeutics. In this systematic review, we selected studies that evaluated the efficacy of such compounds in vivo, using the murine melanoma B16 model. The research was registered at the International Platform of Registered Systematic Review and Meta-Analysis Protocols under the number INPLASY202490019 and conducted using the PubMed, Science Direct, Scopus, and Embase databases, following predefined eligibility criteria and standardized terms from the MeSH and DeCS databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and data were extracted using a Microsoft Excel® spreadsheet. Of the 361 identified studies, 33 were deemed eligible for analysis. Parameters such as routes of treatment administration and induction of melanoma, duration of treatment, and others were collected. The SYRCLE tool was used to identify methodological gaps, such as the absence or insufficient description of randomization and blinding. The results indicated that natural products, especially terpenes, flavonoids, phenolic compounds, quinones, fatty acids, and plant sterols, have considerable antimelanoma activity, with tumor inhibition above 70% and antimetastatic properties. These findings underscore the importance of investigating the potential of these plant compounds as antineoplastic agents and establishing standardized experimental protocols to increase the reliability of the results
