CREBBP, CEBPA, and DNMT3A are tumor suppressor genes whose dysfunction has been reported in hematologic malignancies. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We aim to assess the expression level of CREBBP, CEBPA, and DNMT3A genes in an Egyptian cohort with AML. We investigated the correlation between the selected genes' mRNA levels and their association with clinical characteristics and survival. Herein, 53 adult participants diagnosed with AML were enrolled in the study. Quantitative RT-PCR was used, and computational analysis was added to analyze the relationship between the three genes. CREBBP expression influenced TLC negatively (r = -0.328, p = 0.017). DNMT3A gene expression was found to be significantly associated with CD117 positive (p = 0.028). There was no significant difference between males and females in the relative CREBBP, CEBPA, and DNMT3A expression. Remarkably, AML-M3 cases were devoid of CREBBP expression. The correlation matrix of the three genes detected a significant correlation only between CREBBP and CEBPA expression (r = 0.518, p < 0.0001), though the computational correlation analysis of these two genes was not significant. Our finding may suggest a complementary role of CREBBP and CEBPA in AML pathogenesis; however, further investigation on larger samples is still warranted to study the relationship of these genes with AML survival. We are also reporting here an adult AML case with an additional chromosome 19 as the sole cytogenetic abnormality.