A prospective clinical trial was performed to evaluate the efficacy and tolerance of high-flow nasal cannula (HFNC) in dogs with hypoxemia. 20 client-owned dogs failing conventional oxygen therapy (COT). Patients admitted to the ICU for treatment of hypoxemic respiratory failure were enrolled in the study. PaO2, SPO2, respiratory rate (RR), and acute patient physiologic and laboratory evaluation scores were obtained at the time of COT failure and after initiation of HFNC. Complications and patient tolerance while receiving HFNC were also recorded. Compared to COT, the median PaO2 and SO2 were significantly higher when dogs were receiving HFNC (60.8 vs 135.6 mm Hg and 90.7% vs 99.25%, respectively). Dogs receiving HFNC had a significant reduction in median RR as compared to dogs undergoing COT (52 vs 36 breaths per minute). After the initiation of HFNC, all dogs showed clinical improvement as measured by PaO2, SO2, and RR. Of 20 dogs, 6 ultimately failed HFNC and mechanical ventilation was recommended. Nine dogs undergoing HFNC survived to discharge, and acute patient physiologic and laboratory evaluation scores had a significant positive severity correlation with death. Complications included pneumothorax in 1 dog. COT has limited flow rates due to airway irritation caused by room temperature, nonhumidified oxygen. HFNC uses vapor humidification and heated oxygen, allowing for higher flow rates. In people, HFNC is used as escalation of oxygen therapy when COT fails. Dogs treated with HFNC had significant improvements in PaO2, SO2, and RR as compared to COT. HFNC is well tolerated and effective in treating hypoxemia in dogs.