Musculoskeletal disorders encompass a broad range of conditions that impair movement and physical function. Among them, rheumatoid arthritis and cancer-associated muscle atrophy represent distinct yet critical challenges. While treatments have improved, many patients with arthritis continue to experience persistent inflammation and joint damage, and those with cachexia suffer from progressive muscle wasting with few effective therapeutic options. Our research aims to identify natural bioactive compounds with therapeutic potential for these conditions through high throughput screening and mechanistic evaluation. In arthritis-related studies, we screened various extracts and identified compounds that strongly inhibit IL-1β- and IL-17-mediated inflammatory responses in fibroblast-like synoviocytes (FLS), a central effector in joint pathology. These compounds reduced pro-inflammatory signaling and tissue-destructive phenotypes in both in vitro and in vivo models. For cancer-associated muscle atrophy, we investigated a compound that attenuates muscle loss by targeting key catabolic pathways. In a murine cachexia model, the compound preserved skeletal muscle mass and function by suppressing JAK/STAT-mediated inflammatory signaling, a critical driver of muscle degradation in this context. This presentation will highlight our integrated strategy for identifying and validating natural compounds that act on distinct pathophysiological mechanisms in musculoskeletal diseases. These findings provide insight into potential therapeutic avenues for both joint inflammation and muscle wasting.