Background: Musculoskeletal disorders such as Knee Osteoarthritis (KOA) and Osteoporosis (OP) present significant global health challenges. While the Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) are reliable tools for assessing pain intensity and functional impairment, their molecular underpinnings remain unclear. MicroRNAs (miRNAs), particularly miR-122-5p, have emerged as potential regulators in KOA and OP, with implications for pain perception. Methods: Serum samples from 268 participants were analyzed for miR-122-5p expression, and its correlation with the clinical-radiological parameters was statistically analysed. Results: Despite previous associations between miRNAs and musculoskeletal disorders, miR-122-5p did not exhibit significant correlations with pain/functionality in this study. The findings highlight the complex nature of pain mechanisms and suggest the need for further research to elucidate additional factors influencing pain perception in KOA andpost-menopausal OP. Conclusion: While miR-122-5p did not emerge as a significant molecular player in pain severity/functionality in KOA and post-menopausal OP, this study underscores the need for comprehensive investigations integrating genetic, environmental, and molecular factors to advance personalized interventions for musculoskeletal disorders.