The determination of the critical ventilation flow rate is significant for risk control and standard development during accidental hydrogen leakage in a confined space with hydrogen-related equipment. This paper presents an analytical model for calculating the critical ventilation flow rate through the quantification and constraint solution of the ventilation effect and ventilation cost. The experimental method was used to investigate the effects of nozzle diameter and stagnation pressure on the diffusion and ventilation of horizontal hydrogen leakage in a cuboid chamber. Ventilations from 30 to 180 m3/h were carried out through the rectangular vent. It was shown that the peak concentration of the measuring point was positively correlated with the stagnation pressure and the nozzle diameter. The experimental data were used to verify the analytical model by calculating the effective ventilation time. This study demonstrates that the critical ventilation flow rate can be increased significantly at higher stagnation pressures and larger nozzle diameters. Furthermore, the discrepancy of critical ventilation flow rates under different nozzle diameters will be enhanced with the increase of stagnation pressure. For a stagnation pressure of 0.4 MPa, the critical ventilation flow rate under a 4 mm nozzle even increased by 52% relative to the 2 mm nozzle.