Background: Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and limited treatment options, with chemotherapy resistance posing a significant clinical challenge. UBR5, an E3 ubiquitin ligase, has been consistently reported to be amplified and overexpressed in breast cancers. Materials and methods: This study analyzed 185 TNBC patients to investigate the association between UBR5 expression levels and clinical outcomes. Experimental approaches included in vitro assays using UBR5 knockout or knockdown TNBC cell models treated with doxorubicin and cisplatin, alongside in vivo xenograft models to assess therapeutic responses. Results: High UBR5 expression correlated significantly with poor 5-year disease-free survival (44.0% vs. 82.0% in low UBR5 group) and reduced pathological complete response rates to anthracycline-based neoadjuvant chemotherapy (8.8% vs. 33.3%). In vitro , UBR5 knockout or knockdown sensitized TNBC cells to doxorubicin and cisplatin, enhancing apoptosis and DNA damage accumulation, as evidenced by elevated γ-H2AX levels and impaired DNA damage repair (DDR) pathways, including ATM/CHK2 signaling and key repair proteins (53BP1, RAD51, BRCA1). Mechanistically, UBR5 loss suppressed p38/NF-κB signaling, further compromising DDR and exacerbating chemosensitivity. In vivo , UBR5-deficient xenografts exhibited enhanced doxorubicin responsiveness, an effect mimicked by p38 inhibition. Conclusions: UBR5 serves as a critical mediator of chemoresistance in TNBC by regulating the DNA damage response through the p38 signaling pathway. Targeting UBR5 or p38 signaling presents a promising therapeutic approach to overcome treatment resistance.