Background: Knee osteoarthritis (KOA) is one of the most common chronic muscular diseases in old people. In recent years. ' people are more and more interested in the use of Chinese herbal medicine (CHM) in the treatment of KOA, such as kidney-tonifying and blood-activating medicinal herbs (KTBAMs) in the treatment of KOA. Many studies have confirmed that KTBAMs are effective in the treatment of KOA. However, it is still unknown whether KTBAMs and NSAIDs are more effective in the treatment of KOA. Therefore, we evaluated the efficacy and safety of KTBAMs and NSAIDs in the treatment of KOA. Methods: Randomized controlled trials (RCTs) from online databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Data. and Chinese Biomedical Literature Database that compared the efficacy of KTBAMs and NSAIDs in the treatment of KOA were retrieved. The main outcomes included the evaluation of functional outcomes, pain and adverse effects. The Cochrane risk of bias (ROB) tool was used to assess methodological quality. Results: The literature will provide a high-quality analysis of the current evidence supporting KTBAMs for KOA based on various comprehensive assessments including the total effective rate, visual analog scale scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequence scores, Knee Society Scale (KSS) scores, and adverse effects. Conclusion: This proposed systematic review will provide up-to-date evidence to assess the effect of KTBAMs in the treatment for patients with KOA.