Background: There have been conflicting studies reporting on survival advantages between breast-conserving surgery with radiotherapy (BCS) in comparison with mastectomy. Our aim was to compare the efficacy of BCS and mastectomy in terms of overall survival (OS) comparing all past published studies. Methods: We performed a comprehensive review of literature through October 2021 in PubMed, Scopus, and EMBASE. The studies included were randomized controlled trials (RCTs) and cohorts that compare BCS versus mastectomy. We excluded studies that included male sex, stage 0, distant metastasis at diagnosis, bilateral synchronous cancer, neoadjuvant radiation/chemotherapy, and articles with incomplete data. We performed a meta-analysis following the random-effect model with the inverse variance method. Results: From 18,997 publications, a total of 30 studies were included in the final analysis: 6 studies were randomized trials, and 24 were retrospective cohorts. A total of 1,802,128 patients with a follow-up ranging from 4 to 20 years were included, and 1,075,563 and 744,565 underwent BCS and mastectomy, respectively. Among the population, BCS is associated with improved OS compared with mastectomy [relative risk (RR) 0.64, 95% confidence interval (CI) 0.55–0.74]. This effect was similar when analysis was performed in cohorts and multi-institutional databases (RR 0.57, 95% CI 0.49–0.67). Furthermore, the benefit of BCS was stronger in patients who had less than 10 years of follow-up (RR 0.54, 95% CI 0.46–0.64). Conclusions: Patients who underwent BCS had better OS compared with mastectomy. Such results depicting survival advantage, especially using such a large sample of patients, may need to be included in the shared surgical decision making when discussing breast cancer treatment with patients.