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Objectives To explore whether the addition of HMA to GO could bring additional clinical benefits to AML patients.Background Several studies have shown the HMA plus GO combination showed exciting results. However, the comparison of the clinical efficacy and safety profile of this combination with GO monotherapy has not been witnessed.Methods We performed a systematic review and meta-analysis of 18 clinical trials regarding the mono-GO therapy alone or the HMA + GO combination. The random-effect model or fixed-effect model was applied to the study based on heterogeneity.Results Pooled data of HMA + GO combination are more effective than mono-GO therapy among the unfit acute myeloid leukemia (AML) patients, based on the evaluation of overall response rate (ORR) (HMA + GO vs. mono-GO, 48% vs. 25%), composite complete remission (CRc) (HMA + GO vs. mono-GO, 42% vs. 25%). But pooled data of CRc and ORR showed no notable difference among R/R AML patients. Safety profiles have demonstrated that the HMA + GO combination was tolerable, considering the relatively low toxicities.Conclusion HMA + GO combination, more effective and better tolerated than mono-GO therapy should be recommended to treat unfit AML patients instead of R/R AML patients.