Objective To explore the effect of ultrasound-microbubble mediated miR-128 on doxorubicin resistance in breast cancer cells by regulating PTEN. Methods Quantitatine PCR (qPCR) was used to detect the expression of miR-128 in breast cancer cell lines, and the ultrasound-microbubble combined miR-128 plasmid(plasmid+ultrasound+SF6 microbubbles) was used to transfect the cells to explore the effects of ultrasound-microbubble mediated miR-128 on doxorubicin resistance in cancer cells. The CCK8 experiment was used to detect the activity of breast cancer cells; qPCR was used to detect the effect of overexpression of miR-128 on PTEN and the effect on doxorubicin resistance of breast cancer cells. Results miR-128 was under-expressed in doxorubicin-resistant breast cancer cells; overexpression of miR-128 increased the sensitivity of breast cancer cells to doxorubicin,ultrasound-microbubble mediated miR-128 further enhanced breast cancer cells sensitivity to doxorubicin; miR-128 promote resistance to doxorubicin in breast cancer cells by regulating PTEN. Conclusion Overexpression of miR-128 could enhance the sensitivity of breast cancer to doxorubicin. Ultrasound-microbubble mediated miR-128 further enhanced the sensitivity. This study provided a treatment for doxorubicin resistance in breast cancer with new molecular targets and therapeutic approaches.