AIMS: This study aims to develop a piezoelectric drug delivery system based on hexagonal boron nitride nanosheets (hBNs). MATERIALS AND METHODS: hBNs were synthesized using the chemical vapor deposition (CVD) method and characterized through imaging and spectroscopic techniques. Their piezoelectric properties were evaluated to confirm their functionality. Subsequently, the potential of hBNs as nanocarriers was assessed through in vitro experiments with doxorubicin (Dox) as a model drug. RESULTS: The piezoelectric hBNs were successfully synthesized and exhibited efficient loading and controlled release of Dox. In vitro experiments conducted on PC3 (human prostate cancer) and PNT1A (normal adult prostate epithelial) cell lines demonstrated that ultrasound (US)-induced Dox-loaded hBNs (hBN-Dox) significantly inhibited the proliferation of prostate cancer cells, achieving efficacy at a much lower Dox concentration compared to conventional methods. The system enhanced reactive oxygen species (ROS) generation, impaired cancer cell colony formation, and induced both early and late apoptosis. CONCLUSIONS: These findings highlight the potential of piezoelectric hBNs as nanocarriers for efficient drug delivery, leveraging the synergistic effect of piezoelectricity-induced drug release and the degradation products of hBNs in biological media. Their ability to enhance drug efficacy while reducing the required dose holds promise for advanced cancer therapies.