25 randomized controlled trials with adults diagnosed with knee osteoarthritis were included in this systematic review and meta-analysis comparing glucosamine sulfate, chondroitin sulfate, and their combination against placebo. The pooled outcomes evaluated pain intensity, physical function, joint stiffness, and joint space narrowing. Glucosamine sulfate significantly reduced joint space narrowing but did not significantly affect pain intensity or physical function. Chondroitin sulfate significantly reduced pain intensity and improved physical function. The combination showed no significant benefits over placebo for these outcomes. Both treatments demonstrated good safety profiles. These findings suggest that glucosamine sulfate and chondroitin sulfate individually may provide symptom and disease-modifying effects, but their combination lacks sufficient efficacy.