To explore effects of aging-related genes (ARGs) on the prognosis of Acute Myeloid Leukemia (AML), a seven-ARGs signature was developed and validated in AML patients. The numbers of seven-ARG sequences were selected to construct the survival prognostic signature in TCGA-LAML cohort, and two GEO datasets were used independently to verify the prognostic values of signature. According to seven-ARGs signature, patients were categorized into two subgroups. Patients with high-risk prognostic score were defined as HRPS-group/high-risk group, while others were set as LRPS-group/low-risk group. HRPS-group presented adverse overall survival (OS) than LRPS-group in TCGA-AML cohort (HR=3.39,P<0.001). In validation, the results emphasized a satisfactory discrimination in different time points, and confirmed the poor OS of HRPS-group both in GSE37642 (HR=1.96,P=0.001) and GSE106291 (HR=1.88,P<0.001). Many signal pathways, including immune- and tumor-related processes, especiallyNF-κBsignaling, were highly enriched in HRPS-group. Coupled with high immune-inflamed infiltration, the HRPS-group was highly associated with the driver gene and oncogenic signaling pathway ofTP53. Prediction of blockade therapy targeting immune checkpoint indicated varied benefits base on the different ARGs signature score, and the results of predicted drug response suggested that Pevonedistat, an inhibitor ofNEDD8-activating enzyme, targetingNF-κBsignaling, may have potential therapeutic value for HRPS-group. Compared with clinical factors alone, the signature had an independent value and more predictive power of AML prognosis. The 7-ARGs signature may help to guide clinical-decision making to predict drug response, and survival in AML patients.