The incidence and prevalence of OA have notably increased over the past few decades, particularly in low and middle-income countries, posing significant challenges to the public health systems worldwide. There is an increasing need for innovative diagnostic, monitoring the condition and therapeutic approaches as OA adversely impacts the quality of life in and aging population. Exercise and sports related joint injuries are furthermore increasing. The initial intensity of the injury during exercise and sport is a major determinant of the damage to the joint structures. Even appropriate and timely treatment may cause the early onset of secondary OA in this age group with heightened social and physical expectations. Synovial joint fluid (SJF) emerges as a promising source for monitoring the inflammatory, degenerative and regenerative molecules of the joint microenvironment. By analyzing SJF proteomic and metabolomic profiles, researchers may identify specific biomarkers offering insights into the disease progression and facilitating early diagnosis. In this chapter, we overviewed the published metabolomics and proteomics studies performed on SJF that may reflect the dynamic composition of local pathophysiological processes. Multi-omic approaches may aid the uncovering of novel biomarkers for diagnostic, prognostic and therapeutic purposes. This approach may guide a better definition of the epigenetics, phenotypes and clinical, medicinal and molecular endotypes of OA in the near future. Mapping of various biomedical domains may leverage the comprehensive insight into the disease and/or condition by proteomics and metabolomics may serve as a cutting-edge diagnostic tool in future research and clinical settings.