The role of SETD7（su（var）3–9, enhancer of zeste, trithorax-domain-containing protein 7）methyltransferase in mediating doxorubicin chemotherapy resistance in triple-negative breast cancer （TNBC）was explored. First, TNBC cell lines with SETD7 knockout were constructed using CRISPR-Cas9 gene editing technology. Then, drug sensitivity was assessed through CCK8 assays, cell proliferation was examined via colony formation assays, and apoptosis was measured using flow cytometry. Finally, the levels of apoptosis regulator Bcl-2 and Bax were detected by Western blotting analysis. The results show that SETD7 knockout had no significant impact on TNBC proliferation activity, but SETD7 knockout or the selective inhibitor of SETD7 （R）-PFI-2 increased TNBC sensitivity to the chemotherapeutic drug doxorubicin. In the doxorubicin-treated group, SETD7 knockout significantly reduced TNBC cell proliferation, increased apoptosis levels, and upregulated the apoptosis-relating protein Bax while downregulating Bcl-2 expression. In conclusion, SETD7 enhances TNBC doxorubicin chemotherapy sensitivity by regulating the expression of Bax and Bcl-2 proteins.