Abstract Background Acute myeloid leukemia (AML) is a heterogeneous disorder encompassing a set of hematopoietic tumors that develop when the myeloid precursor cells undergo disproportionate clonal proliferation. Homeobox A 9 (HOXA9) is a pioneer transcription factor in AML pathogenesis along with its cofactor myeloid ecotropic integration site 1 (MEIS1). Our work aimed to evaluate the different expression levels of HOXA9 and MEIS1 genes and their diagnostic and prognostic significance in adult Egyptian patients with de novo AML. The study was carried out on 91 de novo AML Egyptian patients and 41 healthy individuals. Bone marrow samples were obtained from both patients and controls and then tested by reverse transcription-quantitative polymerase chain reaction to assess the mRNA expression in the studied genes. Results HOXA9 and MEIS1 gene expression levels were significantly elevated in AML patients compared to controls (p < 0.001). There was a statistically significant positive correlation between HOXA9 and MEIS1 gene expression in AML patients. However, there was no association between HOXA9 and MEIS1 gene expression levels and disease-free survival (DFS) and overall survival (OS) (p = 0.264 and 0.351, respectively). Conclusion HOXA9 and MEIS1 genes are highly expressed in Egyptian AML patients, suggesting their interesting pathogenic role in AML. They could be used as markers for the diagnosis of AML, but not for the disease prognosis.