Hydrogels that can respond to dynamic forces either from endogenous biological activities or from external mechanical stimuli show great promise as novel drug delivery systems (DDS). However, it remains challenging to engineer hydrogels that specifically respond to externally applied mechanical forces with minimal basal drug leakage under normal stressful physiological conditions. Here we present an ultrasound responsive hydrogel-based DDS with special dual-crosslinked nanoscale network architecture. The covalent crosslinks endow the hydrogel high mechanical stability and greatly suppress deformation-triggered drug release. Meanwhile, the dynamic covalent boronate ester linkages between hydrogel backbone and the anti-inflammation compound, tannic acid (TA), allow effective ultrasound-triggered pulsatile release of TA. As such, the hydrogel shows distinct drug release profiles under compression and ultrasound. A proof-of-principle demonstration of the suppression of inflammation activation of macrophage upon ultrasound-triggered release of TA was also illustrated. We anticipate that this novel hydrogel-based drug delivery system can be used for the treatment of inflammatory diseases on load-bearing tissues, such as muscle and cartilage.