Chronic myeloid leukemia is a myeloproliferative disorder characterized by accumulation of immature cells in bone marrow and peripheral blood. Although successful results were obtained with tyrosine kinase inhibitors, several patients show resistance. For this reason, the identification of new strategies and therapeutic biomarkers represents an attractive goal. The role of Transient Receptor Potential (TRP) ion channels as possible drug targets has been elucidated in different types of cancer. We firstly demonstrated that chronic myeloid leukemia cells express both TRPV1 and TRPV2 receptors. Then, by using FACS analysis, confocal microscopy, gene silencing and cell growth assay, we demonstrated that the activation of TRPV2 by cannabidiol inhibits cell proliferation, induces cell cycle arrest, promotes mitochondria dysfunction and mitophagy. These effects were associated with changes in the expression of OCT-4 and PU.1 markers regulated during cellular differentiation. Interestingly, a synergistic effect by combining CBD with the standard drug imatinib was found. In addition, we also investigated the effects induced by OLDA, a specific TRPV1 agonist and we showed that OLDA induces cell death by stimulating oxidative stress, ER stress, DNA damages and apoptosis. Therefore, the targeting of TRPV1 and 2 could be a promising strategy to enhance conventional therapy and improve the prognosis of CML patients.