Enhancer of zeste homolog 2 (EZH2) shows upregulated expression in tumors and is an important driver of tumor development and progression. However, the mechanism underlying the mediation of tumor aggressiveness by EZH2 remains unclear. We here investigated the levels of EZH2 in various normal and tumorous dog tissues and compared these patterns with those of the corresponding human tissues. Immunohistochemical analysis showed positive staining for EZH2 in 76 of 82 cases of canine tumors, whereas low or negligible staining occurred in normal tissues and other canine tumors, including hepatocellular adenoma and lipoma. In particular, canine lymphoma, melanoma, basal cell tumors, squamous cell carcinoma, and prostate cancer all show EZH2 overexpression, as do their human counterparts. Given the similarities of spontaneous canine tumors to human cancers, we believe that these canine tumors can be used as animal models in future research and clinical trials in the development of EZH2 inhibitors.