Ponatinib is a third-generation tyrosine kinase inhibitor approved for Chronic Myelogenous Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia and it is the only tyrosine kinase inhibitor able to bind T315I mutation of BCR-ABL1 (Breakpoint Cluster Region and Abelson1) kinase protein. However, the cardiotoxic adverse reactions related to Ponatinib treatment can result in serious health problems and discontinuation of the therapy. The underlying mechanisms of Ponatinib-induced cardiotoxicity are not known. This study hypothesized that Ponatinib downregulates leptin and serpine-1 expressions and inhibits angiogenesis through the adipokine-induced p38 MAPK signaling pathway in mouse hearts. To evaluate this proposed pathway C57BL/6J mice were divided into two groups: control and ponatinib. After 14 days of the injections, mice were sacrificed and the heart samples were collected for histological analysis and evaluation of mRNA and protein expression levels. The RNA sequence analysis of heart samples was used to detect the main angiogenic markers affected by the treatment. Further analysis was done by Western Blot, RT-PCR, and immunohistochemistry. The heart function was assessed by echocardiography. Overall, the data indicated that the angiogenic response was inhibited by Ponatinib treatment through leptin and serpine-1-mediated p38 MAPK pathway. The anti-angiogenic response is an important underlying pathological mechanism that could lead to disruption of heart function and the echocardiography data confirmed that ponatinib-treated mice showed impaired heart function. Our study suggested that the potential underlying mechanism of Ponatinib-induced cardiotoxicity can be explained by serpine-1 and leptin-mediated angiogenic pathways.