Background: This retrospective cohort study investigates the prognostic significance of genetic mutations in Chronic Myelomonocytic Leukemia (CMML) and their association with treatment responses among patients treated at a single institution, juxtaposed with a statewide dataset from Kentucky. Methods: The study includes 51 patients diagnosed with CMML under the World Health Organization criteria from January 2005 to December 2023. It examines their genomic profiles and subsequent survival outcomes. The analysis also categorizes patients into CMML-1 and CMML-2 subtypes and assesses survival differences between transformed and non-transformed cases. Results: Mutations in TET2, ASXL1, and SRSF2 were found to significantly influence survival, establishing their roles as critical prognostic markers. Additionally, the cohort from the University of Kentucky exhibited distinct survival patterns compared to the broader Kentucky state population, suggesting that demographic and treatment-related factors could underlie these variances. Conclusions: This research underscores the pivotal role of targeted genetic profiling in deciphering the progression of CMML and refining therapeutic strategies. The findings emphasize the necessity for advanced genetic screening in managing CMML to better understand individual prognoses and optimize treatment efficacy, thereby offering insights that could lead to personalized treatment approaches.