Purpose: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with varying prognostic outcomes. This study aimed to observe potential patterns or association between RUNX1 mutations and clinical features of AML patients, including hyperleukocytosis, thrombocytosis, and 12-month survival outcomes. Methods: A prospective cohort study involving 38 patients diagnosed with de novo AML was conducted at the RSUPN Dr. Cipto Mangunkusumo and Dharmais Cancer Hospital between 2022 and 2023. Patients were followed up for 12 months, and RUNX1 mutations within exons 4, 5, 7, and 8 were detected using polymerase chain reaction (PCR)-Sanger sequencing. Results: This study found RUNX1 mutations in 18.4% of the patients, predominantly in exons 4 and 5. Significant differences in leukocyte counts were observed between patients with and without RUNX1 mutations (p = 0.004). However, no significant association was observed between RUNX1 mutations and hyperleukocytosis or thrombocytosis.Survival analysis revealed that Individuals with RUNX1 mutations had notably lower survival rates (hazard ratio = 6.024, p = 0.014, 95% CI = 1.436–25.279). Conclusion In conclusion, RUNX1 mutations may be associated with poor survival outcomes in Indonesian AML patients. Further studies involving larger cohorts and comprehensive molecular analyses are required to confirm the prognostic significance of these findings.