A novel injectable hydrogel delivery system with high drug loading is developed for prolonged local anesthesia. The system combines heterogeneous microspheres loaded with ropivacaine (HMS-ROP) and an injectable self-healing hydrogel matrix (Gel) to achieve long-term drug release and sustained analgesia. The HMS-ROP microspheres, prepared using a microfluidic chip and in situ alkalization, have a high drug loading capacity of 41.1% and can release the drug over 160 hours in vitro. When combined with the hydrogel matrix and the adjuvant drug dexmedetomidine (DEX), the system provides extended sensory and motor block times of 48 and 36 hours, respectively. The hydrogel-based system exhibits good biocompatibility, self-healing properties, and controlled drug release. In vivo studies show that the system significantly improves the duration of local anesthesia compared to free ROP, with the Gel/HMS-ROP/DEX formulation achieving 36 hours of motor block and 48 hours of sensory block. The system also demonstrates enhanced drug retention, reduced cytotoxicity, and improved biosafety. The hydrogel matrix and microspheres work synergistically to achieve long-term analgesia, making this system a promising approach for postoperative pain management. The study highlights the potential of hydrogel-based drug delivery systems in improving the efficacy and safety of local anesthetics.A novel injectable hydrogel delivery system with high drug loading is developed for prolonged local anesthesia. The system combines heterogeneous microspheres loaded with ropivacaine (HMS-ROP) and an injectable self-healing hydrogel matrix (Gel) to achieve long-term drug release and sustained analgesia. The HMS-ROP microspheres, prepared using a microfluidic chip and in situ alkalization, have a high drug loading capacity of 41.1% and can release the drug over 160 hours in vitro. When combined with the hydrogel matrix and the adjuvant drug dexmedetomidine (DEX), the system provides extended sensory and motor block times of 48 and 36 hours, respectively. The hydrogel-based system exhibits good biocompatibility, self-healing properties, and controlled drug release. In vivo studies show that the system significantly improves the duration of local anesthesia compared to free ROP, with the Gel/HMS-ROP/DEX formulation achieving 36 hours of motor block and 48 hours of sensory block. The system also demonstrates enhanced drug retention, reduced cytotoxicity, and improved biosafety. The hydrogel matrix and microspheres work synergistically to achieve long-term analgesia, making this system a promising approach for postoperative pain management. The study highlights the potential of hydrogel-based drug delivery systems in improving the efficacy and safety of local anesthetics.