Chronic Myeloid Leukemia (CML) is marked by the BCR::ABL1 fusion gene. Monitoring tyrosine kinase inhibitor (TKI) therapy response is crucial for treatment management, thus, limitations in Reverse Transcription quantitative PCR's (RT-qPCR) accuracy and sensitivity led to the exploration of alternative methods like digital PCR (dPCR). This study evaluated dPCR efficacy in detecting Minimal Residual Disease (MRD) in CML patients undergoing TKI therapy. 79 CML patients were enrolled (NP 3809 clinical trial), with samples analysed using both methods. The achievement and stability of Deep Molecular Response (DMR) were assessed over a 2-year period following the first DMR achievement. A comparative statistical analysis of MRD and DMR attainment, stability, and potential TFR achievement using both RT-qPCR and dPCR was conducted, supported by chi-squared tests, Fisher's exact tests, and Kaplan-Meier analysis. In 69/79 patients, dPCR either anticipated or coincided DMR achievement as compared to RT-qPCR. Among them, 52/69 achieved a stable DMR according to RT-qPCR, while 44/69 according to dPCR. Thus, dPCR capability to anticipate or coincide the achievement of a stable DMR resulted with p = 0.0012 and p = 0.0017, respectively. Transcript type and TKI choice did not influence DMR achievement or stability by either method. These findings highlight dPCR as a sensitive and accurate tool for monitoring MRD in CML patients, providing information for treatment management decisions, and potentially enhancing the selection of candidates for treatment-free remission. Further standardization of dPCR methodologies is warranted to leverage their benefits in clinical practice.