Brain metastases from breast cancer represent a serious complication, associated with reduced survival and impaired quality of life. Increased patient survival and the limited ability of the blood-brain barrier to be crossed by systemic therapies have led to a rising incidence of these lesions. The molecular profile of metastases may differ from that of the primary tumor in approximately 29% of cases, significantly influencing the choice of targeted treatment. In this retrospective study, we included 100 women who underwent craniotomy for breast cancer brain metastases between 2015 and 2020 at the Prof. Dr. Nicolae Oblu Neurosurgery Clinic, Iași. We recorded demographics (age, residence), latency from primary diagnosis to brain metastasis, and MRI features (number, location, edema, hemorrhage). Histopathology and immunohistochemistry included GATA3, CK5/6, ER, PR, HER2, and Ki-67 using standardized protocols. ER/PR positivity was defined as ≥1% nuclear staining; HER2 was scored 0–3+ per ASCO/CAP; Ki-67 was reported as a percentage index. The most frequent metastatic subtypes were HER2-positive (32%) and triple-negative (25%). The mean Ki-67 index was 48.2% and showed a significant inverse correlation with the time from primary breast cancer diagnosis to brain metastasis (r = –0.57; P < 0.001). Higher Ki-67 values were associated with hemorrhagic lesions, while lower values occurred in solitary metastases. Patients receiving hormonal therapy had longer median survival (29.5 months) compared to those receiving targeted therapy (11.9 months; P < 0.001). Immunohistochemical profiling of brain metastases from breast cancer, focusing on ER, PR, HER2, and Ki-67, revealed specific correlations between tumor proliferation, time to metastasis, and neuroimaging features such as hemorrhage and lesion location. HER2-positive and triple-negative subtypes showed higher brain metastatic potential and poorer outcomes with targeted therapy, while luminal tumors responded better to hormonal treatment. The inverse correlation between Ki-67 and metastasis latency, as well as its association with aggressive imaging phenotypes, represents an original contribution of this study, underscoring the need for tailored therapeutic strategies based on combined pathological and imaging data.