<jats:sec><jats:title>Purpose</jats:title><jats:p>High‐intensity focused ultrasound (HIFU)‐mediated drug release becomes a promising therapeutic technique for treatment of cancer, which has merits of deep penetration, noninvasive approach and nonionizing radiation. However, conventional thermocouple‐based approach for treatment monitoring would encounter big challenges such as the viscous heating artifact and difficulty in monitoring in the deep region. In this study, we develop an effective method based on thermal strain imaging (TSI) for the evaluation of HIFU‐mediated drug release.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Both phantom experiments and preliminary animal experiments were performed to investigate the feasibility of the proposed approach. Doxorubicin (DOX)‐loaded cerasomes (HIFU and temperature‐sensitive cerasomes, HTSCs) were prepared. In the phantom experiments, the HTSC solution is contained inside a cylindrical chamber within a tissue‐mimicking phantom. In the animal experiments, the HTSCs are intravenously injected into tumor‐bearing mice. An HIFU transducer is used to trigger DOX release from the HTSCs within the phantom or mice, and TSI is performed during HIFU heating. In the phantom experiments, the accuracy of temperature estimation using TSI is validated by measuring with a thermocouple. In animal experiments, the spatial consistency between the distribution of DOX released within the tumor and the location of the heating region estimated by TSI is validated using a spectrofluorophotometer.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the phantom experiments, the HTSCs show a burst release of DOX when the temperature of the HTSC solution estimated by TSI reaches about 42°C, which is in agreement with the condition for drug release from the HTSCs. The temperature estimation using TSI has high accuracy with error below 2.5%. In animal experiments, fluorescence imaging of the tumor validates that the heating region of HIFU could be localized by the low‐strain region of TSI.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The present framework demonstrates a reliable and effective solution to the evaluation of HIFU‐mediated local drug delivery.</jats:p></jats:sec>