M. S. Afariogun Bioactive compounds, ethnopharmacology, hepatoprotective, herbal medicine, nephroprotective 49-57 9 (3) July 2025 Phyllanthus amarus (Stonebreaker) has been utilized for centuries across diverse traditional medicine systems, including Ayurveda, African herbal medicine, and South American folk remedies, for the treatment of renal and gastric disorders. This review critically evaluates its ethnopharmacological applications, phytochemical composition, pharmacological mechanisms, clinical efficacy, and safety profile. Clinical studies support its efficacy in managing kidney stones (demonstrating a 58% stone-free rate in recent trials), liver disorders (with 38% HBsAg reduction in hepatitis B patients), and metabolic conditions, though concerns regarding dose-dependent nephrotoxicity warrant further toxicological evaluation. Emerging applications in nanotechnology-enhanced drug delivery, precision medicine, and synergistic combination therapies present promising avenues for future research. By synthesizing traditional knowledge with contemporary scientific validation, this review highlights the potential of P. amarus as a bridge between ethnopharmacology and evidence-based medicine, while identifying critical gaps in standardization, long-term safety assessment, and clinical translation that require further investigation.