Phase-change nano-droplet (PCND) was found to promote cavitation and aid the active oxygen generation by sonochemical agents. PCNDs, which are droplets containing superheated perfluorocarbon, were suspended in buffer solution with a dye sensitizer, Rose Bengal (RB). Samples were exposed to 1.1-MHz ultrasound with a sequence consisting of pulses for generating microbubbles and continuous waves for inducing cavitational effects. The yield of reactive oxygen species (ROS) by ultrasound exposures, measured as the increase of fluorescence intensity of a fluorescein derivative was strongly dependent on the interval of the pulses. It was found that pulse intervals shorter than 0.03 s were needed to generate ROS. Further, we found that RB works not only for generating ROS but also for inducing cavitation. Because PCNDs have been revealed to significantly reduce cavitation threshold both in vitro and in vivo, the combination of PCNDs and dye sensitizers may lead to a sonodynamic tumor treatment method with reduced ultrasound energy and improved reproducibility.