Six dogs with massive hepatocellular carcinoma that was not amenable to surgery were treated by oral administration of single-agent toceranib at a dose of 2.0–3.0 mg/kg every other day for a minimum of 60 days. Partial response was achieved in three dogs, stable disease was achieved in one dog, and progressive disease occurred in two dogs, according to the canine Response Evaluation Criteria in Solid Tumors v1.0. Observed adverse events were mild to moderate in severity and reported in accordance with the Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events v1.1. Activities of alanine aminotransferase and alkaline phosphatase decreased in the cases that were sensitive to treatment with toceranib, whereas the activities remained high in resistant cases. Additionally, the level of phospho-vascular endothelial growth factor receptor 2 was found to be increased in a resistant case. Single-agent toceranib might prove to be an effective treatment for canine hepatocellular carcinoma pending further validation.