Sustainable maize production under changing climatic conditions, especially heat and water stress conditions is one of the key challenges that need to be addressed immediately. The current field study was designed to evaluate the impact of water stress on morpho-physiological, biochemical, reactive oxygen species, antioxidant activity and kernel quality traits at different plant growth stages in maize hybrids. Four indigenous i.e., YH-5427, YH-5482, YH-5395, JPL-1908, and one multinational maize hybrid i.e., NK-8441 (Syngenta Seeds) were used for the study. Four stress treatments (i) Control (ii) 3-week water stress at pre-flowering stage (iii) 3-week water stress at anthesis stage (iv) 3-week water stress at grain filling/post-anthesis stage. The presence of significant oxidative stress was revealed by the overproduction of reactive oxygen species (ROXs) i.e., H2O2 (1.9 to 5.8 µmole g−1 FW) and malondialdehyde (120.5 to 169.0 nmole g−1 FW) leading to severe negative impacts on kernel yield. Moreover, a severe reduction in photosynthetic ability (50.6%, from 34.0 to 16.8 µmole m−2 s−1), lower transpirational rate (31.3%, from 3.2 to 2.2 mmol m−2 s−1), alterations in plant anatomy, reduced pigments stability, and deterioration of kernel quality was attributed to water stress. Water stress affected all the three studied growth stages, the pre-flowering stage being the most vulnerable while the post-anthesis stage was the least affected stage to drought stress. Antioxidant activity was observed to increase under all stress conditions in all maize hybrids, however, the highest antioxidant activity was recorded at the anthesis stage and in maize hybrids YH-5427 i.e., T-SOD activity was increased by 61.3% from 37.5 U mg−1 pro to 60.5 U mg−1 pro while CAT activity was maximum under water stress conditions 8.3 U mg−1 pro as compared to 10.3 U mg−1 pro under control (19.3%). The overall performance of maize hybrid YH-5427 was much more promising than other hybrids, attributed to its higher photosynthetic activity, and better antioxidant defense mechanism. Therefore, this hybrid could be recommended for cultivation in drought-prone areas.