<p>Acute myeloid leukemia (AML) and <i>DNMT3A</i> mutations (<i>DNMT3A</i>^mut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in <i>DNMT3A</i>-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by <i>NPM1</i> and <i>FLT3</i>-ITD status revealed worse survival among patients with <i>NPM1</i> mutations and wild-type <i>FLT3</i>-ITD (<i>NPM1</i>^mut/<i>FLT3-</i>ITD^wt) than patients in the ELN-2022 favorable risk group. The other three subgroups (<i>NPM1</i>^mut/<i>FLT3-</i>ITD^mut, <i>NPM1</i>^wt/<i>FLT3-</i>ITD^mut, and <i>NPM1</i>^wt/<i>FLT3-</i>ITD^wt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of <i>TET2</i>^mut in patients with AML and <i>DNMT3A</i>^mut/<i>NPM1</i>^mut/<i>FLT3</i>-ITD^wt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with <i>TET2</i>^mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with <i>MMP14</i>, <i>CD200</i>, and <i>CT45A5</i> identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with <i>DNMT3A</i>^mut. Patients with <i>TET2</i>^mut constituted a unique subgroup within the ELN-2022 favorable <i>DNMT3A</i>^mut/<i>NPM1</i>^mut/<i>FLT3</i>-ITD^wt group, characterized by distinct transcriptomic features and an unfavorable prognosis.</p>