Abstract Background Approximately one in six women in the USA takes antidepressants and a third use selective serotonin reuptake inhibitors (SSRIs) after breast cancer diagnosis. Recent investigation demonstrated serotonin receptor (5-HTR2B) expression in the breast and serotonin production as an indicator of poor breast cancer prognosis. This study investigates the association between SSRI use at different time intervals relative to breast cancer diagnosis on survival. Methods A population-based sample of 6959 consecutive, newly diagnosed breast cancer cases in Northern Israel was included. Patients were recruited from January 2000 and followed up through March 2020. Participants completed risk factor questionnaires regarding medical, reproductive and family history, medication use and health habits. Full prescription data were available through the Israeli national Clalit medical database. Multivariate Cox proportional hazard models were used to determine survival based on time of SSRI use. Results Use of SSRIs in the 5 years prior to breast cancer diagnosis was associated with a 66% increase in overall mortality (HRadj = 1.66; CI: 1.05–2.63). SSRI use that initiated after breast cancer diagnosis was associated with an 81% increase in mortality (HRadj = 1.81; CI: 1.58–2.06). Use of SSRIs in the 5 years post-diagnosis was associated with a dose–response increase (P < 0.001) in long-term mortality (>5 years). Heavy SSRI use (≥24 prescription fills) after diagnosis was associated with nearly doubling in mortality (HR = 1.99; CI: 1.39–2.83). Conclusion SSRI use prior to and after breast cancer diagnosis is associated with increased mortality in breast cancer patients. Additional research is needed to better understand mechanisms mediating this association.