Introduction High-flow nasal cannula (HFNC) has increased exercise capacity in patients with chronic respiratory diseases. However, it remains unknown whether HFNC impacts respiratory physiological variables during exercise. This study aimed to evaluate the effect of HFNC on respiratory physiological variables during sustained high-intensity exercise in healthy volunteers. Methods We performed a single-centre, open-label, randomised crossover trial to compare HFNC (60 L·min−1) and Sham-HFNC (2 L·min−1) interventions during a constant work rate exercise (CWRET) through randomised order. The primary outcome was change in oesophageal pressure (ΔPoes), and the secondary outcomes were other variables of inspiratory effort, ventilation distribution, ventilatory variables and clinical assessment. We evaluated volunteers at seven time points (baseline=T0; CWRET=T1-T2-T3 (1, 4 and 6 min); cooldown period=T4-T5-T6 (1, 6 and 10 min)) in both interventions. Results 14 healthy volunteers (50% women; age: 22 (21–27) years) were enrolled. Mean differences in ΔPoes decreased to favour the HFNC intervention compared to Sham-HFNC at T2 (−2.8 cmH2 O; 95% CI −5.3 to −0.3), as well as the simplified oesophageal pressure–time product (sPTP) per minute at T2 (−86.1 cmH2 O·s·min−1; 95% CI −146.2 to −26.1) and T3 (−79.9 cmH2O·s·min−1; 95% CI −142.3 to −17.6). The standard deviation of the Regional Ventilation Delay index was also lower with HFNC compared to Sham-HFNC (T1: −1.38; 95% CI −1.93 to −0.83; T2: −0.71; 95% CI −1.27 to −0.16). There was decreased dyspnoea to favour the HFNC, but sPTP per breath, spatial distribution ventilation indexes, ventilatory variables and clinical assessments were nonsignificant between interventions. Conclusion HFNC intervention reduces respiratory effort and dyspnoea and improves temporal ventilation distribution in healthy volunteers during CWRET.