The combined therapy strategy of venetoclax with hypomethylating agents (HMAs) has demonstrated encouraging efficacy in the treatment of acute myeloid leukemia (AML), particularly in elderly patients or those deemed unfit for standard treatments. However, due to differences in the research focuses of various research centers, the results have not yet comprehensively and systematically demonstrated the clinical significance of this treatment approach. Therefore, in this meta-analysis, we aimed to assess the effectiveness and safety of venetoclax in combination with HMAs for the treatment of AML. We included a total of 20 clinical studies that met the search criteria, including research focused on AML patients carrying FLT-3 and IDH mutations. Results revealed an overall response (OR) rate of 0.57 and a complete remission (CR)/complete remission with incomplete marrow recovery (CRi) rate of 0.52. Subgroup analyses indicated varying CR/CRi rates among patients with different genetic mutations, with the highest rate observed in IDH mutation carriers at 0.71, FLT-3 mutation carriers at 0.64, and TP53 mutation carriers at 0.44. Simultaneously, we observed adverse events such as anemia, neutropenia, and thrombocytopenia, underscoring the importance of careful management during venetoclax and HMAs treatment. This study emphasizes the potential of venetoclax and HMAs as a promising therapeutic approach for AML while highlighting the critical need for monitoring and managing adverse events in such treatment regimens.