Although sonodynamic therapy (SDT) has shown promise for cancer treatment, the lack of efficient sonosensitizers (SSs) has limited the clinical application of SDT. Here, a new strategy is reported for designing efficient nano-sonosensitizers based on 2D nanoscale metal–organic layers (MOLs). Composed of Hf-oxo secondary building units (SBUs) and iridium-based linkers, the MOL is anchored with 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) sensitizers on the SBUs to afford TBP@MOL. TBP@MOL shows 14.1- and 7.4-fold higher singlet oxygen (¹O₂) generation than free TBP ligands and Hf-TBP, a 3D nanoscale metal–organic framework, respectively. The ¹O₂ generation of TBP@MOL is enhanced by isolating TBP SSs on the SBUs of the MOL, which prevents aggregation-induced quenching of the excited sensitizers, and by triplet–triplet Dexter energy transfer between excited iridium-based linkers and TBP SSs, which more efficiently harnesses broad-spectrum sonoluminescence. Anchoring TBP on the MOL surface also enhances the energy transfer between the excited sensitizer and ground-state triplet oxygen to increase ¹O₂ generation efficacy. In mouse models of colorectal and breast cancer, TBP@MOL demonstrates significantly higher SDT efficacy than Hf-TBP and TBP. This work uncovers a new strategy to design effective nano-sonosensitizers by facilitating energy transfer to efficiently capture broad-spectrum sonoluminescence and enhance ¹O₂ generation.