Objective Model-based virtual experiments with different output flows delivered by high flow nasal cannula (HFNC), the respiratory mechanical parameters of the patient in acute respiratory distress syndrome (ARDS) would be investigated for discussing the therapeutic and side effects of the HFNC. Method Consequently, with using the Matlab, a ventilation system model of HFNC including the sub-model of HFNC device and sub-model of respiratory patient in ARDS was developed for simulation experiments. In the experiments, the ARDS patient with different lung compliances was set. The ventilations of HFNC were carried out for collecting and analyzing the data of respiratory mechanical parameters. And the simulation-based outcomes were discussed comparing to the outcomes get in physical experiments. Results The experiments illustrated: Increasing the output flow of HFNC, the relevant respiratory mechanical parameters of respiratory flow (Q) and tidal volume (Vt) will be tendentiously decreased, but the intrapulmonary pressure (Plung) and the functional residual capacity (FRC) will be increased; At the condition of small flow, the output flow from HFNC may be smaller than the inspiratory airflow required by the patient. Conclusions Summarily, under treatment with the HFNC applied in ARDS patient, increasing the output flow of HFNC will tendentiously reduce the Q and Vt, but rise the Plung and FRC. The necessary compensation in inspiration to make up for a lack of gas will promote the security of HFNC. Understanding the changing in the respiratory mechanical parameters of ARDS patient will be beneficial to pre-evaluate the HFNC, to improve the treatment effect of HFNC, and to reduce the risks of HFNC.