Abstract Background A high‐flow nasal cannula (cHFNC) delivers flow continuously (during inspiration and expiration). Using the diaphragm electrical activity (Edi), synchronizing HFNC could be an alternative (cycling high/low flow on inspiration/expiration, respectively). The objective of this study was to demonstrate the feasibility of synchronized HFNC (sHFNC) and compare it to cHFNC. Methods Different levels of cHFNC and sHFNC (4, 6, 8, and 10 liters per minute [LPM], with 2 LPM on expiration for sHFNC) were compared in eight rabbits (mean weight 3.16 kg), before and after acute lung injury (pre‐ALI and post‐ALI). Edi, tracheal pressure (Ptr), esophageal pressure (Pes), flow, and arterial CO 2 were measured. In addition to the animal study, one 3.52 kg infant received sHFNC and cHFNC using a Servo‐U ventilator. Results In the animal study, there were more pronounced decreases in Edi, reduced Pes swings and reduced PaCO 2 at comparable flows during sHFNC compared to cHFNC both pre and post‐ALI ( p < .05). Baseline (pre‐inspiratory) Ptr was 2−7 cmH 2 O greater during cHFNC ( p < .05) indicating more dynamic hyperinflation. In one infant, the ventilator performed as expected, delivering Edi‐synchronized high/low flow. Conclusion Synchronizing high flow unloaded breathing, decreased Edi, and reduced PaCO 2 in an animal model and is feasible in infants.