Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is pivotal in treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), particularly in cases involving the T315I mutation, which promotes resistance to earlier TKI generations. Ponatinib effectively inhibits the mutated breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog (ABL) kinase, by circumventing the steric hindrance from this mutation. However, its extensive off-target effects often lead to cardiotoxicity, presenting as arterial occlusive events, heart failure, and hypertension, which have raised significant clinical concerns. Studies indicate that ponatinib-induced cardiotoxicity may result from its impact on cell survival pathways, inflammation, and the integrated stress response. Despite Food and Drug Administration (FDA) approval, adverse cardiovascular outcomes have led to dose adjustments and an exploration of alternative treatment strategies. Current research focuses on mitigating ponatinib’s cardiotoxic effects through co-therapies and structural analogs, aiming to balance efficacy against the T315I mutation with a safer cardiovascular profile. This review explores ponatinib’s development as a TKI, clinical trials, structure, mechanisms of action, and toxic side effects, especially cardiotoxic effects, highlighting potential therapeutic strategies for reducing cardiovascular risks while maintaining anticancer efficacy.