Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging.