A vortex whistle produces a fundamental frequency proportional to the inlet flowrate. Recent investigations using vortex whistles have focused on the use of this relationship to quantify aspects of respiratory function. Despite promising results, there is a lack of understanding of the physical mechanisms underlying vortex whistle function. This paper begins with a principled study of the aero-acoustic properties of the vortex whistle. First, a high-fidelity computational fluid dynamics (CFD) simulation was developed to predict the unsteady flow field induced by the vortex whistle when the expiratory flow is applied. A computational aero-acoustic analysis (CAA) was applied to predict the acoustic response of the vortex whistle and to capture the frequency and level of the signature spectral peaks. The CFD is validated against prior experimental data on the vortex whistle. The CFD was used to: (a) determine the source of the vortex whistle harmonics and (b) investigate the effect of an outlet tube terminator, proposed by Awan and Awan (2020, “Use of a Vortex Whistle for Measures of Respiratory Capacity,” J. Voice). The CFD and CAA indicated that the harmonics are generated by the cylindrical cavity of the vortex whistle, and the outlet terminator increases harmonic signal-to-noise ratio by increasing the pressure fluctuation within the cylindrical cavity. These results support the addition of the outlet tube terminator and provide insight into future design modifications that will enhance the reliability of the vortex whistle analyses and enable additional measures of respiratory capacity.