Abstract Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) and a key extracellular matrix (ECM) component of cartilage, ligaments, and connective tissues, essential for mechanical resilience, cartilage elasticity, and joint lubrication. In osteoarthritis (OA) and rheumatoid arthritis (RA), CS plays a dual role as both a structural stabilizer and an anti-inflammatory modulator. Mechanistically, it promotes ECM synthesis by stimulating proteoglycans and type II collagen, suppresses cartilage-degrading enzymes (MMP-1, -3, -13), and reduces synovial inflammatory mediators such as IL-1β, IL-6, TNF-α, PGE₂, and nitric oxide. CS also improves synovial viscosity, provides antioxidant protection, and protects subchondral bone integrity, making it a foundational nutrient for structural joint care. Clinical evidence demonstrates that supplementation with 200-800 mg/day CS improves WOMAC scores, slows joint space narrowing, and alleviates morning stiffness with superior safety compared to NSAIDs. Randomized trials confirm its structural benefits in OA, adjunctive value in RA, and supportive effects in cervical/lumbar degeneration, synovitis, and exercise-induced joint stress. Within multi-nutrient formulations such as Keyora JointOra 5 in 1, Chondroitin sulfate (250 mg/day) synergizes with UC-II (immune tolerance), glucosamine sulfate (substrate supply), hyaluronic acid (synovial lubrication), and vitamin D₃ (immune regulation), forming a comprehensive repair network that integrates immune modulation, cartilage reinforcement, and synovial support. Target populations include aging adults with OA, RA patients in remission, individuals with synovitis or morning stiffness, athletes under repetitive load, sedentary workers with spinal degeneration, and NSAID-intolerant populations. Overall, CS represents a safe, multi-pathway structural and functional intervention with broad clinical applicability for long-term joint resilience.