Background and Objective <p>This systematic review and meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of knee osteoarthritis (KOA), particularly in relation to weight reduction, pain relief, and functional improvement. KOA is a prevalent and disabling condition worldwide, often exacerbated by obesity-related mechanical and inflammatory factors. Given the weight-reducing and anti-inflammatory properties of GLP-1RAs—originally developed for type 2 diabetes and obesity—they are being explored as potential therapeutic agents in KOA.</p> Method <p>We conducted a comprehensive search of MEDLINE, Embase, and CENTRAL databases up to January 15, 2025 to identify randomized controlled trials (RCTs) evaluating GLP-1RAs in adult KOA patients. Studies were included if they compared GLP-1RAs with placebo and reported outcomes related to body weight, pain, or physical function. Data were pooled using a random-effects model, and the risk of bias was assessed using the Cochrane Risk of Bias 2 tool.</p> Results <p>Two RCTs with a total of 563 participants met the inclusion criteria. Both trials assessed semaglutide or liraglutide compared to placebo. Patients receiving GLP-1RAs showed significant reductions in body weight (− 7.56&#xa0;kg; 95% CI: − 14.71 to − 0.41) and BMI (− 4.51&#xa0;kg/m²; 95% CI: − 9.02 to − 0.01). Gastrointestinal adverse effects were the most commonly reported side effects. While trends toward improvement in pain and physical function were observed, the small number of trials limited the strength of conclusions regarding these outcomes.</p> Conclusion <p>GLP-1RAs may offer a promising approach for KOA management by addressing both obesity and inflammatory mechanisms. However, the evidence is currently limited by the small number of available studies, particularly regarding symptomatic outcomes such as pain and function. Larger, long-term trials are needed to establish their full therapeutic potential in KOA.</p>