Abstract: Knee osteoarthritis (KOA) is a prevalent chronic degenerative joint disorder characterized by an imbalance between articular cartilage degradation and synthesis, a central mechanism in KOA pathogenesis. Given the absence of disease-modifying therapies, there is a critical need to elucidate the underlying pathological processes, establish reliable biomarkers for early detection and prognosis, and identify safer, more effective therapeutic agents. In recent years, natural products have attracted considerable interest due to their low toxicity, cost-effectiveness, and distinct biological activities, demonstrating significant potential in KOA management. These compounds can impede KOA progression through multiple mechanisms, including promoting cartilage matrix synthesis, mitigating inflammation, reducing oxidative stress, suppressing chondrocyte apoptosis, and modulating autophagy, thereby supporting their translational application. This review summarizes biomarkers relevant to early diagnosis and phenotypic stratification in KOA, with a focus on elucidating the pharmacological actions and molecular mechanisms of natural products, such as flavonoids, alkaloids, saponins, terpenes, and traditional Chinese medicine (TCM) formulas, in KOA intervention, aiming to provide evidence-based strategies for improved disease management.