ABSTRACT: Injectable hydrogels derived from decellularized extracellular matrix (ECM) are emerging biomaterials for minimally invasive tissue repair. Among available sources, human placental tissue is appealing due to its abundance, ethical acceptability, and structural similarity to fetal tissue environments. In this study, we developed and evaluated hydrogels derived from decellularized human placental extracellular matrix (PECM), with and without crosslinking using tannic acid (TA), to enhance their mechanical strength and therapeutic performance. A perfusion-based decellularization protocol, combining enzymatic and detergent treatments, effectively removed cellular material while preserving key matrix components, such as collagen and glycosaminoglycans. The ECM was then freeze-dried, cryo-milled, and enzymatically digested to form hydrogels at concentrations of 10, 15, and 20 mg/mL, which were neutralized and gelled at body temperature (37 °C). To reinforce structure and functionality, the hydrogel was crosslinked with TA, a natural polyphenol known for its biocompatibility and antioxidant effects. TA-crosslinked hydrogels showed significantly improved mechanical properties, including higher storage modulus and slower degradation, while maintaining excellent injectability. Proteomic analysis confirmed the presence of regenerative proteins such as Serpin E1 and IGFBP1, indicating retention of bioactive signaling cues. In vitro, these hydrogels supported healthy growth of endothelial and fibroblast cells, showed good blood compatibility, and exhibited antioxidant and antibacterial activity, particularly in the crosslinked formulations. In vivo experiments in both healthy and diabetic mouse wound models showed that 15 mg/mL PECM hydrogels, especially those with TA, accelerated wound healing, enhanced blood vessel formation, reduced inflammation, and promoted tissue regeneration. Overall, this work offers a reproducible and scalable approach to creating bioactive, mechanically resilient hydrogels. The combination of optimized ECM concentration and TA crosslinking provides a versatile platform for next-generation injectable treatments in regenerative medicine.