Purpose Combining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2− breast cancers. Here, we performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2− breast cancer. Method A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, ≥ G3–G4 adverse events (AEs), and G3–G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model. Results Eight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50–0.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43–0.61) significantly improved the PFS of metastatic HR+/HER2− breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52–0.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24–0.47). The use of these drugs was characterized by a significant increase of G3–G4 AEs (OR 10.88, 95% CI 6.53–18.14). Conclusion Emerging data provide a new standard treatment for advanced HR+/HER2− breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.