Background: Breast cancer is the most common cancer in women, and the majority of breast cancers express the estrogen receptor or progesterone receptor. Inhibition of CDK4/6 signaling pathway has shown survival benefit in advanced breast cancer by overcoming endocrine therapy resistance. Yet, there are considerable hematologic toxicities associated with CDK 4/6 inhibitors and hence, we performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018 were queried. RCTs that mention anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II studies) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: anemia, 3.494 (95% CI: 2.535–4.814; P<.0001); thrombocytopenia, 6.066 (95% CI: 3.055–12.046; P<.0001); leukopenia, 10.376(95% CI: 7.236–14.879; P<.0001); and neutropenia, 14.387 (95% CI: 10.877–19.031; P<.0001). The RR of high-grade adverse effects were as follows: anemia, 2.251 (95% CI: 1.393–3.637; P=.001); thrombocytopenia, 3.696 (95% CI: 1.417–9.642; P=.008); leukopenia, 22.083(95% CI: 12.126–40.217; P<.0001); neutropenia, 33.527(95% CI: 17.271–65.082; P<.001). Neutropenic fever was noted in 71 (3.73%) in CDK 4/6 inhibitors group vs 28 (2.18%) in control arm. The pooled RR was statistically significant at 12.056 (95% CI: 1. 352–3.127; P=.001) and RD was 0.014 (95% CI: −0.002–0.029; P=.078) Conclusion: CDK 4/6 inhibitors–based regimen significantly contributed to all hematologic toxicities as well as febrile neutropenia. The improved efficacy outcomes and manageable toxicities with CDK 4/6 inhibitors are observed with proper supportive care and close monitoring.