A new noninvasive method for the detection of DNA damage using mid-to high-frequency ultrasound (10-60 MHz) has been developed. Ultrasound imaging and quantitative analysis methods are used to detect cell death occurring in response to anticancer therapies in cell samples in vitro, in rat brain tissue ex vivo, and in cancer mouse models in vivo. Experimental evidence indicates that the mechanism behind this ultrasonic detection is linked to changes in the size and acoustic properties of the cell nucleus occurring with forms of cell death, and in particular apoptosis. Nuclear changes associated with cell death can result in up to 16-fold increase in ultrasound backscatter intensity and changes in spectral slope that are consistent with theoretical predictions. Furthermore, color-coded images can be generated based on specific ultrasound parameters in order to identify the regions of cell death in tumor ultrasound images with treatments. These results provide a foundation for future investigations regarding the use of ultrasound in preclinical and clinical settings to noninvasively monitor tumor responses to specific interventions that induce cell death.