Macrophages play a distinctive role in the early stage of inflammation after cartilage defects. Previous studies have shown that macrophages can express different phenotypes, among which M2 polarization is important to maintain the balance of the inflammatory microenvironment and promote cartilage regeneration. In this study, 4-octyl itaconic acid (4-OI), a derivative of the endogenous metabolite itaconic acid, was used to regulate the polarization behavior of macrophages and enhance cartilage repair. Oxidized sodium alginate (OSA) and gelatin (GEL) were selected as materials to form injectable hydrogels with the function of sustained release of 4-OI. In vivo and in vitro experiments have verified that the OSA/GEL hydrogel system loaded with 4-OI could promote M2 macrophage polarization and inhibit the inflammatory reaction. A rat knee joint cartilage defect model further confirmed its role in promoting cartilage regeneration in the later stage. In this study, the OSA/GEL hydrogel was successfully fabricated as a vehicle for delivering 4-OI, which could evidently alleviate the inflammatory reaction and thus accelerate tissue regeneration. The results of this study provide a new method for promoting subsequent tissue regeneration by regulating the early immune response.