Opioids are potent analgesic agents, frequently being used to manage severe pain associated with musculoskeletal (MSK) trauma. The adverse effects of systemic opioids, such as respiratory depression, development of dependency and tolerance have impeded clinical opioid utility. To overcome these limitations, we have developed N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrugs (ProGel-HMP) of hydromorphone (HMP) as a novel peripherally restricted analgesic agent for local management of MSK pain. In the present study, ProGel-HMP formulations were synthesized and characterized for their physicochemical properties. The localized retention and tissue biodistribution were assessed using near-infrared (NIR) optical imaging in a mouse model of closed femoral fracture. Analgesic efficacy was evaluated through static weight-bearing (incapacitance test) and dynamic gait analysis (CatWalk XT) over three weeks post-ProGel-HMP administration. Potential systemic analgesia was assessed via tail-flick latency. The risk of respiratory depression was evaluated using whole-body plethysmography in rats. Quantitative micro-computed tomography (micro-CT) was performed at 6 weeks post-ProGel-HMP treatment to screen for any potential impacts on the fracture healing process. NIR optical imaging confirmed that local intra-callus injection of ProGel-HMP resulted in its sustained retention at the fracture site for at least 14 days. A single local administration of ProGel-HMP provided sustained pain relief, maintaining balanced static weight distribution and improved dynamic gait parameters for up to 21 days post-fracture, whereas dose-equivalent free HMP lost efficacy within 2 days. Tail-flick testing demonstrated substantially reduced systemic antinociceptive activity following ProGel-HMP administration compared with dose-equivalent free HMP. Whole body plethysmography revealed no significant impairment in respiratory rate, tidal volume, or minute ventilation. Quantitative micro-CT analysis verified that ProGel-HMP treatment did not compromise the fracture healing process, with similar callus morphology, bone mineral density, and microstructural parameters when compared to controls. In conclusion, intra-callus administration of thermoresponsive ProGel-HMP provides potent and sustained local analgesia in a closed femoral fracture mouse model. These findings support ProGel-HMP’s potential as a promising peripherally restricted analgesia for pain management in orthopaedic trauma.