Chronic pain is a prevalent condition affecting a significant portion of the global population and is known to be associated with an increased risk of cardiovascular diseases. Despite the clinical relevance, the mechanisms underlying the link between chronic pain and myocardial ischemia-reperfusion (MI/R) injury remain poorly understood. This study aimed to investigate the role of the superior cervical ganglion (SCG) in mediating the effects of chronic pain on MI/R injury and to develop a novel therapeutic strategy. We identified that chronic pain upregulated TNF-α expression and induced hyperactivity in SCG sympathetic neurons, exacerbating MI/R injury. To address this, we engineered an injectable Pluronic/alginate-based composite hydrogel loaded with celecoxib and ropivacaine (celecoxib@Laponite-dopamine-alginate-Pluronic F-127@ropivacaine, CLDAFR). This hydrogel was designed to target the SCG, providing a localized and sustained release of the therapeutic agents, thereby mitigating neuronal inflammation and inhibiting neuronal hyperactivity. The CLDAFR hydrogel demonstrated excellent biocompatibility, heat-sensitive gelation properties, and controlled drug release in vitro. In vivo studies showed that applying CLDAFR effectively reduced MI/R injury in a chronic pain model by suppressing TNF-α expression and SCG neuronal activity. In conclusion, the CLDAFR hydrogel represents a promising therapeutic material for treating chronic pain-exacerbated MI/R injury by precisely targeting the SCG and providing a sustained anti-inflammatory and analgesic effect.