Urothelial carcinoma (UC) is the most common form of bladder cancer in both humans and dogs. Treatment options for UC often have variable response rates with only 50% of patients responding long term. Evidence suggests cannabinoids, both endogenous and plant based, are potent anti-cancer therapies with potential to enhance current treatments. However, their potential benefits have not been explored in UC. It was determined that cannabidiol (CBD), a phytocannabinoid, synergizes chemotherapy treatment. Further, combination with radiation therapy demonstrated CBD’s potential to radiosensitize UC cell lines. Finally, inhibition of MAGL, a metabolic enzyme in the endocannabidiome, impaired migration and invasion conferring a less aggressive phenotype. These findings suggest that cannabinoids may be novel anti-cancer therapies for both canine and human UC. Further studies are required to confirm these results in more complex models.