Objective To explore the clinical efficacy of azacytidine + venetoclax in the treatment of elderly patients with relapsed refractory acute myeloid leukemia (AML). Method The present study included 20 elderly patients with relapsed refractory AML from January 2019 to January 2021. These patients were randomized into treatment groups (n = 10, azacytidine alone) and control groups (n = 10, azacytidine + venetoclax) by a random number table. The differences in efficacy, adverse reactions, hematology parameters, and immune functions in elderly patients with relapsed refractory AML in two groups were analyzed. Results The total efficiency for elderly patients with relapsed refractory AML was 90.00% and significantly higher than that in the control group (40.00%), P 0.05; the incidences of adverse reactions were not significantly different between the two groups, P > 0.05. Conclusion Azacytidine + venetoclax in the treatment of elderly patients with relapsed refractory AML could improve efficacy and hematology parameters with high safety, which is of great significance.