Introduction The restricted duration is a fundamental drawback of traditional local anesthetics during postoperative pain from a single injection. Therefore, an injectable local anesthetic that produces repeatable on-demand nerve blocks would be ideal. Methods We offer ultrasound-triggered on-demand analgesia consisting of dendritic mesoporous silica nanoparticles (DMSN) carried with ultrasound-sensitive perfluoropentane (PFP) and levobupivacaine (DMSN-bupi-PFP) to achieve repeatable and customizable on-demand local anesthetics. Results The vaporization of liquid PFP was triggered by ultrasound irradiation to produce a gas environment. Subsequently, the enhanced cavitation effect could improve the release of levobupivacaine to achieve pain relief under a moderate-intensity ultrasound irradiation. DMSN-bupi-PFP demonstrated a controlled-release pattern and showed a reinforced ultrasonic sensitivity compared to levobupivacaine loaded DMSN (DMSN-bupi). The sustained release of levobupivacaine produced continuous analgesia of more than 9 hours in a model of incision pain, approximately 3 times longer than a single free levobupivacaine injection (3 hours). The external ultrasound irradiation can trigger the release of levobupivacaine repeatedly, resulting in on-demand analgesia. In addition, DMSN-bupi-PFP nanoplatforms for ultrasound-enabled analgesia showed low neurotoxicity and good biocompatibility in vitro and in vivo. Conclusion This DMSN-bupi-PFP nanoplatform can be used in pain management by providing long-lasting and on-demand pain alleviation with the help of moderate-intensity ultrasound.