Drought is considered as a significant stress that hampers growth, development as well as productivity of wheat crop around the globe. The present investigation was performed to determine the changes induced by drought on morpho-physiology, antioxidative system, metabolism and yield parameters in wheat crop. The study also focussed on evaluating the effect of zinc-chitosan-salicylic acid (ZCS) nanoparticles in alleviating physiological and biochemical alterations and overcoming yield losses caused by drought. Drought was provided during the vegetative stage on four different varieties (two drought tolerant viz. C-306 and PBW-644 and two drought susceptible viz. HUW-322 and HUW-843) by withholding irrigation and maintaining moisture capacity of soil at 40%. ZCS nanoparticles were foliar sprayed on wheat at concentrations of 100, 200 and 400 mg L−1. Application of ZCS nanoparticles at 100 mg L−1 significantly (p < 0.05) enhanced relative water content (RWC), alleviated levels of antioxidative enzymes like superoxide dismutase, ascorbate peroxidase, glutathione reductase and guaiacol peroxidase and metabolites like proline, ascorbate, malondialdehyde and flavanoid in wheat leaves subjected to drought. Drought recovery was noteworthy in tolerant as well as sensitive varieties. Water stress reduced grain yield / plant by nearly 45% in tolerant varieties and nearly 50% in sensitive varieties. Spray of the nanoparticles on wheat foliage incremented the yield to 63% and 41% in tolerant varieties and 50% and 46% in sensitive varieties. This study suggests an outstanding role of ZCS nanoparticles at a concentration of 100 mg L−1 in mitigation of ill effects of drought. These nanoparticles have the ability to improve osmotic status of plant, enhance synthesis of osmoprotectants, activate ROS scavenging enzymes for maintaining membrane integrity and cellular protection and promote yield increment during drought stress. This implicates its role in ensuring food security and sustainable agriculture with reduction in environmental pollution due to limited use of fertilizers.