Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by elevated mortality. Epigenetic therapy plays an essential role in the treatment of AML. However, the clinical outcomes of the combination of multiple epigenetic agents and conventional chemotherapy remain unclear. We conducted a phase 2 study to evaluate the clinical safety and efficacy of chidamide combined with CAG and venetoclax-azacitidine (referred to as CACAG-VEN) in AML patients (NCT05659992). Patients received induction treatment with aclarubicin (10 mg/m²/d on days 1, 3, and 5), azacitidine (75 mg/m² on days 1-7), cytarabine (75 mg/m² bid on days 1-5), chidamide (30 mg, twice/week for 2 weeks), and venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on days 3-14). Granulocyte colony-stimulating factor 5 μg/kg/day was administered. After one cycle of CACAG-VEN, the overall response rate was 96.7 %, with a composite complete response (CRc) rate of 93.3 %. The CRc rates (86.7 %) were remarkable among patients with adverse NCCN risk. Patients receiving two cycles of CACAG-VEN achieved a CRc rate of 100 %. The 12-month overall survival rate was 69.7 %. The median time to recovery was 19 days for platelets ≥50,000/μL and 17 days for an absolute neutrophil count ≥500 cells/μL after induction therapy. The single-cell RNA sequence showed most immune cells exhibited no significant change in proportion after removing tumor cells. In conclusion, this regimen resulted in a high CRc rate in newly diagnosed AML patients, particularly in adverse-risk patients. And this regimen had minimal impact on immune cells.