On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve blocks in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve blocks to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produced reactive oxygen species that reacted with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. Repeatable ultrasound-triggered nerve blocks were achieved in vivo, with the nerve-block duration depending on the extent and intensity of insonation. There was no detectable systemic toxicity and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the management of relatively localized pain states and could potentially minimize opioid use.