We present a woman in her 30s with sickle cell disease (SCD) treated with monthly exchange transfusions who had suffered cerebrovascular complications, presented with a 4-cm left breast mass and was ultimately diagnosed with Estrogen receptor-positive, human epidermal growth factor receptor 2 positive (ER+HER2/Neu+) invasive ductal carcinoma with axillary metastasis. She was treated with neoadjuvant trastuzumab-based chemotherapy, followed by a left-modified radical mastectomy and had residual invasive disease. She received postmastectomy radiation followed by adjuvant trastuzumab emtansine. Given the ER positivity, she also began adjuvant ovarian suppression (OS) and an aromatase inhibitor (AI). Throughout treatment, her SCD remained well-controlled, highlighting the potential for effective and tolerable cancer therapy in patients with SCD and the importance of interdisciplinary collaboration. This case underscores the importance of tailored oncological management and the need for further research on chemotherapy safety in this population.