Background: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Current standard-of-care primarily relies on cytotoxic chemotherapy and radiotherapy, but long-term outcomes remain poor largely due to early relapse, therapy resistance, and high incidents of metastases. More recently, dopamine signaling has emerged as a novel area of interest in cancer biology. Dopamine receptors have been implicated in tumor progression, maintenance of cancer stem-like cells, and therapy resistance in various malignancies, including TNBC. Quetiapine (QTP), an FDA-approved atypical antipsychotic and DRD2/DRD3 antagonist, has shown preclinical efficacy in glioblastoma. However, its anti-tumor potential in TNBC remains unexplored. Methods: Clonogenic survival and mammosphere-forming assays were used to evaluate QTP\'s anti-tumor activity in TNBC cell lines (SUM159-PT, BT-549, and MDA-MB-231). Cells were treated with QTP alone or in combination with a single dose of 4 Gy radiation or standard chemotherapeutic agents (doxorubicin, paclitaxel, 5-fluorouracil). Apoptotic cell death was evaluated using Annexin V/propidium iodide flow cytometry, while DNA double-strand breaks were assessed through gamma-H2AX staining. Transwell assays were conducted to examine QTP\'s impact on both untreated bulk tumor cells and those surviving sublethal radiation exposure. Additionally, the effect of QTP on DNA repair dynamics was investigated by monitoring the resolution of gamma-H2AX foci over time following treatment. Results: QTP significantly reduced clonogenicity and self-renewal in all TNBC models tested, both alone and in combination with radiation or chemotherapy. In apoptosis assays, QTP treatment induced a marked increase in early and late apoptotic cell populations. QTP also promoted DNA double-strand break formation and delayed repair, as indicated by persistent gamma-H2AX foci at 24 hours post-treatment. Additionally, QTP impaired the migratory capacity of both untreated and radiation-surviving cells. Combination treatments with QTP and doxorubicin produced synergistic effects, resulting in complete loss of colony-forming ability and mammosphere formation. Conclusions: The data presented in this study support the repurposing of quetiapine as an adjuvant therapeutic agent alongside radiotherapy and chemotherapy in TNBC. By targeting apoptosis, DNA repair, and cancer cell migration, QTP offers a novel, multi-faceted approach to improving outcomes in this high-risk breast cancer subtype.