Improving plant water use efficiency (WUE) by osmoprotectant represents the main approach to sustainable productivity. Field trials were conducted to elucidate the efficiency of glycinebetaine (GlyBet) concentrations (0, 200, 400, 600 mg/l) for overcoming drought injury (1500, 1200, and 900 m3/fed) on potato plant productivity. Drought stress significantly decreased potato plant growth (plant height, and leaves number, leaf area, axillary stem number/plant, as well as foliage fresh weight, leaves dry matter), photosynthetic pigment (chlorophyll a, chlorophyll b, and carotenoid), ion% (nitrogen, phosphorous, and potassium), and yield components (tuber weight plant-1, tuber number plant-1, marketable and non-marketable yield). Alternatively, drought significantly increased antioxidant enzyme activity, non-marketable yield, tuber dry matter, tuber hardness and densely, vitamin C, and total soluble solids associated with boosting WUE. The greatest reduction was documented under severe drought. Foliar spraying with GlyBet significantly increased all growth and yield traits except non-marketable yield which is decreased. Additionally, GlyBet spraying increased photosynthetic pigment and proline concentration, ion percentage, and activity of antioxidant enzymes associated with improving relative water content and WUE. The greatest values were recorded with 600 mg/l GlyBet application over other concentrations or nontreated plants. Regarding the interaction effects, the current findings revealed that GlyBet supplementation at all concentrations utilization alongside 1200 and 900 m3/fed, nullifies the drastic impact on plant growth and productivity as well as some biochemical trails. Accordingly, 600 mg/l GlyBet foliar spraying as an eco-friendly and cost-effective osmoprotectant twice has the potential to mitigate drought injury and increase WUE.