In the evolving therapeutic landscape of chronic myeloid leukemia (CML), asciminib stands out as a critical treatment option. Its ability to bind to and allosterically modulate the myristoyl pocket of BCR::ABL1 enables asciminib to effectively overcome resistance to conventional tyrosine kinase inhibitors (TKIs). Asciminib has shown significant cytogenetic and molecular responses in heavily pretreated patients, those previously exposed to ponatinib, and treatment-naïve individuals, attributed to its pharmacological selectivity and generally favorable safety profile. Asciminib also offers a compelling alternative for patients with a history of cardiovascular events or unfavorable cardiovascular profiles. However, extended follow-up in ongoing trials is necessary for a thorough assessment of its long-term benefits. Mutations in the myristoyl pocket, such as A337V/T and I502L, along with kinase domain mutations, including F359C/I/V at the kinase-SH2 interface and M244V in the N-lobe, have demonstrated the ability to undermine asciminib effectiveness in clinical practice, highlighting the importance of mutational assessment before starting treatment. This review provides an in-depth analysis of the preclinical and clinical evidence supporting the use of asciminib, synthesizing findings from a targeted literature search of PubMed and Web of Science. Our discussion integrates insights into its mechanism of action, clinical efficacy, safety, resistance patterns, and future directions.