Therapeutic plasma exchange (TPE) is a cornerstone extracorporeal therapy with broad immunomodulatory effects across diverse immune-mediated and inflammatory diseases. By removing circulating pathogenic substances such as autoantibodies, immune complexes, complement components, and pro-inflammatory cytokines, TPE rapidly interrupts humoral pathways driving tissue injury. This review summarizes the mechanisms through which plasma exchange modulates immune activity, including both depletion of harmful plasma factors and restoration of normal homeostatic proteins when donor plasma is used. Biomarker analyses demonstrate predictable reductions in immunoglobulins, cytokines, and complement activity, reflecting the profound but transient immune reset achieved with TPE. Comparisons with related apheresis modalities, such as immunoadsorption, double filtration plasmapheresis, and extracorporeal photopheresis, highlight the unique advantages of TPE as a broadspectrum immunomodulatory intervention. Clinically, TPE remains a vital therapeutic option in conditions ranging from thrombotic thrombocytopenic purpura and myasthenia gravis to vasculitis and cytokine storm syndromes. As evidence and technology evolve, plasma exchange continues to exemplify how biophysical removal of pathogenic plasma constituents can effectively restore immune balance and improve patient outcomes in both acute and chronic immune-mediated diseases.