Phase-change nano-droplet (PCND) was found to promote chemically significant cavitation. PCNDs, which were droplets containing superheated perfluorocarbon and suspended in buffer solution with potassium iodide, were exposed to 1.1-MHz ultrasound with a sequence of periodically applied triggering pulses to generate microbubbles and following continuous-wave (CW) exposures. The chemical activity of ultrasound exposures, measured as the reaction yield of tri-iodide ions was strongly dependent on the interval of the pulses. We found that pulse intervals shorter than 0.03 s were needed to generate chemically significant cavitation. Further, we found that pre-exposure of ultrasound for chemical effects could be performed by using gel phantoms with thermal coagulation indicators, without sacrificing the effect of PCNDs to enhance temperature increase induced by exposure to high intensity focused ultrasound (HIFU). The results we obtained suggested the potential of 'chemo-thermal' therapy for tumors, which sequentially utilizes the chemical and thermal effect of PCNDs.