A methodology to predict the onset of flow instability (OFI) in a single horizontal microtube with an inlet orifice is developed based on the predication of pressure drop. The predictive methodology states, for the same flow rate, the flow instability occurs as the single-phase liquid pressure drop under no heating condition equals the two-phase pressure drop under heating condition in a single microtube. The addition of inlet orifice increases the heat flux at the onset of flow instability by increasing the upstream pressure. The present methodology is validated by comparing the predicted heat flux at the onset of flow instability with our previous experimental data in the microtubes with three sizes of inlet orifices. The results show that the present method can predict the heat flux at the onset of flow instability with a deviation of 30% and mean absolute error of 13% at mass fluxes from 700 to 3000 kg/m2 s. The effects of inlet orifice size and saturation pressure on the onset of flow instability are also studied based on the present methodology. It is found that, at mass fluxes from 100 to 2000 kg/m2 s, the area ratio less than 15% eliminates the flow instability completely before the critical heat flux occurs.