Background Mast cell tumors (MCT) are common cutaneous tumors in dogs and when not amenable to surgical excision can present a therapeutic challenge. New treatment protocols for unresectable MCT are needed. Hypothesis The combination of toceranib, prednisone, and hypofractionated radiation treatment (RT) will be well tolerated and efficacious. Animals Seventeen client-owned dogs with measurable MCT amenable to RT. Methods Prospective clinical trial. All dogs received prednisone, omeprazole, diphenhydramine, and toceranib. Toceranib was administered for 1 week before initiating RT, consisting of 24 Gy delivered in 3 or 4 fractions. Results On an intent-to-treat basis, the overall response rate was 76.4%, with 58.8% of dogs achieving a complete response and 17.6% a partial response. The median time to best response was 32 days, and the median progression-free interval was 316 days. The overall median survival time was not reached with a median follow-up of 374 days. The most common toxicoses were gastrointestinal and hepatic. Conclusions and Clinical Importance The combination of hypofractionated RT, toceranib, and prednisone was tolerated and efficacious in the majority of dogs. Response rates and durations were higher than those reported for toceranib as a single-agent treatment for MCT. This combination is a viable treatment option for unresectable MCT.