OBJECTIVE To determine the effect of high-flow nasal cannula (HFNC) oxygen therapy on cardiorespiratory variables and outcome in dogs with acute hypoxemic respiratory failure. METHODS Prospective, sequential clinical trial. METHODS University veterinary teaching hospital. METHODS Twenty-two client-owned dogs that failed to respond to traditional oxygen support. METHODS Initiation of HFNC therapy after traditional oxygen supplementation failed to increase Spo2 > 96% and Pao2 > 75 mm Hg or improve respiratory rate/effort. RESULTS Physiological variables, blood gas analyses, and dyspnea/sedation/tolerance scores were collected prior to HFNC initiation (on traditional oxygen support [time 0 or T0]), and subsequently during HFNC oxygen administration at time 30 minutes, 60 minutes, and 7 ± 1 hours. Relative to T0, use of HFNC resulted in a decreased respiratory rate at 1 hour (P = 0.022) and 7 hours (P = 0.012), a decrease in dyspnea score at all times (P < 0.01), and an increase in Spo2 at all times (P < 0.01). There was no difference in arterial/venous Pco2 relative to T0, although Paco2 was correlated with flow rate. Based on respiratory assessment, 60% of dogs responded to HFNC use by 30 minutes, and 45% ultimately responded to HFNC use and survived. No clinical air-leak syndromes were observed. CONCLUSIONS HFNC use improved oxygenation and work of breathing relative to traditional oxygen therapies, without impairing ventilation. HFNC use appears to be a beneficial oxygen support modality to bridge the gap between standard oxygen supplementation and mechanical ventilation.