Background/Objectives: Imatinib, a first-generation tyrosine kinase inhibitor, is the standard treatment for chronic myeloid leukemia (CML). Although generic formulations have improved access, concerns regarding their efficacy and safety remain. This study aimed to compare the clinical outcomes and adverse events of original and generic imatinib in patients with CML in Thailand. Methods: We conducted a retrospective cohort study of patients with chronic-phase CML receiving frontline imatinib at Chiang Mai University Hospital between January 2012 and September 2022. Treatment responses, event-free survival (EFS), overall survival (OS), and adverse events were also analyzed. Results: Among the 71 patients, 46 (64.8%) received original imatinib, and 25 (35.2%) received generic imatinib. The median follow-up period was 80.3 months (IQR: 52.0–106.4). At 12 months, there were no significant differences in the cumulative complete cytogenetic response (73.3% vs. 70.8%, p = 0.825) or major molecular response (35.6% vs. 41.7%, p = 0.618). Although EFS was not significantly different between the groups, OS was significantly longer in patients receiving original imatinib (p < 0.001). Conclusions: Although early treatment responses and EFS were similar, generic imatinib was associated with an inferior OS. These findings highlight the need for close monitoring and further evaluation of long-term outcomes when using generic formulations.