Background Breast cancer is one of the common global health concerns that affects2.1 million women each year and causes the highest number of cancer-related morbidity and mortality among women. The objective of this study was to determine the mortality rate and its predictors among breast cancer patients at the referral hospitals, in northwest Ethiopia. Methods A retrospective follow-up study was conducted on breast cancer patients registered between February 01, 2015 and February 28, 2018. They were selected by simple random sampling using computer-generated method and followed until February 29, 2020, in Amhara region referral hospital. A pre-tested data extraction checklist was used to collect data from the registration book and patient medical records. The collected data were entered into Epi-Data version 3.1 and exported to STATA version 14 for analysis. The mortality rate by person-year observation was computed. The Kaplan-Meier survival curve with the log-rank test was used to estimate the survival probabilities of the patients. Bivariate and multivariate Cox regression model was used to identify predictors of mortality. Results The overall mortality rate of breast cancer was 16.9 per 100 person-years observation. The median survival time was 38.3 (IQR: 26.23, 49.4) months. Independent predictors of breast cancer mortality was; Clinical stage IV and stage III (aHR:10.44,95% CI: 8.02,11.93 and aHR: 9.43, 95% CI: 6.29,11.03respectively), number of positive lymph node in the category of 10 and more and number of positive lymph node within the category of 4–9 (aHR:12.58, 95%CI: 5.2, 30.46 and aHR: 4.78, 95% CI: 2.19, 10.43respectively), co-morbidities (aHR:1.5, 95%CI: 1.01,2.21), Postmenopausal (aHR:2.03,95% CI: 1.37, 3), histologic grade III (aHR:2.12, 95% CI: 1.26,3.55) and not received hormonal therapy (aHR: 2.19, 95%CI: 1.52,3.15) were independent predictors of mortality. Conclusion The overall mortality rate was 16.9 per 100 person-years. The finding was higher compared to high-income countries. Advanced clinical stage, co-morbidities, menopausal status, and hormonal therapy are the significant predictors of mortality. Early detection and treatment of breast cancer is needed to reduce the mortality rate.