Background Acute myeloid leukemia (AML) is the most common acute blood malignancy in adults. The complicated and dynamic genomic instability (GI) is the most prominent feature of AML. Our study aimed to explore the prognostic value of GI-related genes in AML patients.Methods The mRNA data and mutation data were downloaded from the TCGA and GEO databases. Differential expression analyses were completed in limma package. GO and KEGG functional enrichment was conducted using clusterProfiler function of R. Univariate Cox and LASSO Cox regression analyses were performed to screen key genes for Risk score model construction. Nomogram was built with rms package.Results We identified 114 DEGs between high TMB patients and low TMB AML patients, which were significantly enriched in 429 GO terms and 13 KEGG pathways. Based on the univariate Cox and LASSO Cox regression analyses, seven optimal genes were finally applied for Risk score model construction, including SELE, LGALS1, ITGAX, TMEM200A, SLC25A21, S100A4 and CRIP1. The Risk score could reliably predict the prognosis of AML patients. Age and Risk score were both independent prognostic indicators for AML, and the Nomogram based on them could also reliably predict the OS of AML patients.Conclusions A prognostic signature based on seven GI-related genes and a predictive Nomogram for AML patients are finally successfully constructed.