The temporal and quantitative control of the cargo release is a challenging issue in the application of hydrogels for cancer therapy. Here, we report hyaluronic acid hydrogel-based depot that provides ultrasound-triggered thermal elevation and on-demand cargo release. The hyaluronic acid hydrogel was developed by employing the gold cluster as a sonothermal crosslinker which was grown on the cargo to prevent its undesired leakage until ultrasound-induced dissociation. The results demonstrated that, in the presence of ultrasound at 30 W, the hyaluronic acid hydrogel significantly increased the temperature to 53.7 °C, leading to dissociation of gold clusters and subsequent cargo release. In addition, the prepared hydrogel exhibited appropriate mechanical properties and superior biostability as an injectable hydrogel for in vivo applications.