The recent food security issues, combined with the threats from climate change, demand future farming systems to be more precise and accurate to fulfill the ever increasing global food requirements. The role of nutrients such as nitrogen (N), phosphorous (P), and potassium (K) in stimulating plant growth and development is well established; however, little is known about their function, if applied in combination, in improving crop yields under environmental stresses like drought. The aim of this study was to evaluate the effects of combined foliar spray of supplemental NPK (NPKc) on physiological and biochemical mechanisms that enhance the drought tolerance potential of wheat for improved yield. Foliar NPKc markedly influenced the accumulation of osmoprotectants and activity of both nitrogen assimilation and antioxidant enzymes. It significantly improved the concentration of proline (66 %), total soluble sugars (37 %), and total soluble proteins (10 %) and enhanced the activity of nitrate reductase, nitrite reductase, catalase, and peroxidase by 47, 45, 19, and 8 %, respectively, with respect to no spray under water-deficit conditions which, in turn, improve the yield and yield components. The accumulation of osmolytes and activity of antioxidant machinery were more pronounced in drought tolerant (Bhakkar-02) than sensitive genotype (Shafaq-06).