Drought stress often occurs concurrently with heat stress, yet the interacting effect of high vapor pressure deficit (VPD) and soil drying on the physiology of potato plants remains poorly understood. This study aimed to investigate the physiological and growth responses of potatoes to progressive soil drying under varied VPDs. Potato plants were grown either in four separate climate-controlled greenhouse cells with different VPD levels (viz., 0.70, 1.06, 1.40, and 2.12 kPa, respectively) or under a rainout shelter in the field. The VPD of each greenhouse cell was caused by two air temperature levels (23 and 30 °C) combined with two relative humidity levels (50 and 70%), and the VPD of the field was natural conditions. Irrigation treatments were commenced three or four weeks after planting in greenhouse cells or fields, respectively. The results indicated that soil water deficits limited leaf gas exchange and shoot dry matter (DMshoot) of plants while increasing the concentration of abscisic acid (ABA) in the leaf and xylem, as well as water use efficiency (WUE) across all VPD levels. High VPD decreased stomatal conductance (gs) but increased transpiration rate (Tr). High VPD increased the threshold of soil water for Tr began to decrease, while the soil water threshold for gs depended on temperature due to the varied ABA response to temperature. High VPD decreased leaf water potential, leaf area, and DMshoot, which exacerbated the inhibition of soil drying to plant growth. Across the well-watered plants in both experiments, negative linear relationships of gs and WUE to VPD and positive linear relations between Tr and VPD were found. The results provide some novel information for developing mechanistic models simulating crop WUE and improving irrigation scheduling in future arid climates.