Abstract: Rhubarb (Rheum spp.), a traditional herbal medicine, has attracted growing interest due to its anti-renal fibrosis effects in chronic kidney disease (CKD). This review systematically evaluates Rhubarb’s botanical features, global distribution, and diverse processing methods, which influence its chemical composition and bioactivity. Major bioactive constituents, including anthraquinones, stilbenes, and polyphenols, are cataloged, and their potential roles in renal protection are elucidated. Traditional applications in nephropathy management are critically assessed alongside contemporary pharmacological evidence demonstrating Rhubarb’s ability to attenuate renal fibrosis. Notably, this review highlights that multiple bioactive components in Rhubarb exert potent anti-fibrotic effects through complex, interactive modulation of multiple signaling pathways. Despite promising preclinical data, clinical translation remains limited by insufficient understanding of pharmacokinetics and potential herb-drug interactions. This synthesis identifies key research gaps, advocating for interdisciplinary studies to decipher multi-target mechanisms, refine pharmacokinetic profiles to enhance bioavailability, and translate preclinical findings into randomized controlled trials (RCTs). By integrating ethnopharmacological knowledge with modern drug discovery frameworks, this review underscores Rhubarb’s potential as a multifaceted anti-fibrotic agent while calling for methodologically rigorous research to validate its therapeutic integration into CKD management protocols.