Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and alterations in subchondral bone, ultimately leading to chronic pain and impaired mobility. This study aimed to identify plasma proteomic alterations in OA patients before and after arthroplasty in order to reveal biomarkers associated with both ongoing disease processes and postoperative recovery. The study cohort consisted of eighteen individuals: eight OA patients undergoing total knee or hip arthroplasty and ten healthy controls matched for age, sex, and body mass index. Plasma samples were depleted of high-abundance proteins, enzymatically digested, and subsequently analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) to characterize proteomic changes.