Abstract Purpose of Review This review aims at outlining alpha-2-macroglobulin (A2M) injection, a novel non-operation strategy which could delay the process of osteoarthritis (OA). Meanwhile, some burning issues concerning “experimental” and “applied” are also indicated in this review. Recent Findings Many researchers have found that the alpha-2-macroglobulin, a sort of broad-spectrum proteinase inhibitor, presents remarkable inhibitive effect on intra-articular inflammation. Additionally, results of animal experiments prove that the A2M can postpone cartilage degeneration. Some treatments, such as hyaluronic acid (HA), which have been applied clinically for many years proved not to be as effective; thus, the advantage of A2M is presented. Summary A2M promises to be a new strategy of non-operative treatment of OA for its excellent anti-inflammation effect and biosafety. Better improved pharmaceutical preparations and treatment strategies shall be developed with the in-depth research.