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Simple Summary: The renin–angiotensin system (RAS) is a well-known hormonal system that controls blood pressure and blood volume. Recent work has suggested that it also plays a role in cancer. Various studies in humans and animals have investigated blocking different parts of the RAS; many, but not all, studies have shown decreased tumor growth and spread. The RAS consists of various bypass pathways, which may explain the lack of a response to treatment in some studies. A treatment has been developed to simultaneously block multiple parts of the RAS (multimodal blockade). This treatment has been used in one clinical trial in humans with glioblastoma (a brain tumor) and another trial in cats with squamous cell carcinoma (skin cancer). The aim of this study was to assess the safety of multimodal blockade of the RAS in dogs with two different types of cancer (osteosarcoma and oral malignant melanoma). Two mild adverse effects were observed: one dog developed intermittent vomiting; another dog had a mildly increased serum SDMA concentration (a kidney function biomarker) at one time point. This sets the stage for conducting a larger-scale trial to assess the efficacy of this treatment for cancer in dogs. The renin–angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer. [ABSTRACT FROM AUTHOR]