BackgroundKnee osteoarthritis (KOA) stands as a prevalent clinical condition that frequently affects individuals. A growing body of research has highlighted the potential advantages of dietary supplements, including glucosamine and chondroitin, in the management of KOA.PurposeThis study aims to ascertain the most efficacious dietary supplement for KOA, with a specific focus on reducing pain, alleviating stiffness, and enhancing joint function.MethodsWe conducted an exhaustive search of multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library, from inception to May 2023. We specifically focused on randomized controlled trials (RCTs) comparing various dietary supplements with the placebo group within the context of KOA. Assessment of outcomes among these groups relied on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), with weighted mean differences (WMDs) and associated 95% confidence intervals (CIs) computed. Network meta-analyses were employed to compare outcomes across different supplement groups in comparison with the placebo. The surface under the cumulative ranking curve (SUCRA) was utilized to rank these supplements.ResultsOur comprehensive analysis included 22 studies with 2,777 participants in total. The outcomes from our network meta-analysis yielded the following key findings: To reduce the total WOMAC score, the top three interventions were E-OA-7, LParActin, and LcS. For reducing the WOMAC score of pain, the most effective interventions were Aflapin, NEM, and PFP. In addressing the reduction of the WOMAC score of stiffness, NEM, Aflapin, and MSM emerged as the optimal interventions. Finally, for diminishing the WOMAC score of physical function, the most effective interventions were E-OA-7, LParActin, and LcS.ConclusionIn comparison to the placebo, NEM (for stiffness), Aflapin (for pain), and E-OA-07 (for knee function and WOMAC total score) were discerned as the most effective interventions for the treatment of KOA.Clinical trial registrationhttps://www.crd.york.ac.uk/prospero/.