Methemoglobinemia secondary to administration of hydroxyurea is only reported in veterinary medicine as a result of accidental ingestion of high doses, and once at therapeutic dose in human medicine. A 2.5-year-old female spayed mixed breed dog was presented for acute signs of neurologic disease and diagnosed with severe erythrocytosis without an identified underlying cause, leading to suspicion of polycythemia vera. The dog was managed with phlebotomies, supportive care, and administration of hydroxyurea. Within 2 h of administration of hydroxyurea (37 mg/kg) administration, respiratory distress with cyanosis, and methemoglobinemia developed. Signs resolved within 24 h but recurred after a second administration of lower dosage of hydroxyurea (17 mg/kg) 20 days later. The dog remained asymptomatic except for mild cyanosis but was humanely euthanized for lack of relevant improvement of signs of neurologic disease. This case report documents the repeated occurrence of methemoglobinemia in a dog after administration of hydroxyurea at therapeutic doses.