Lack of water at limiting levels results in drought stress, which may have an impact on the various stages of a crop's life cycle. Four different genotypes of snapmelon (Cucumis melo L. var. momordica) responded differently to 0, 7 and 21 d of simulated drought stress. Information was collected on a range of morpho-physiological, biochemical and molecular characteristics. Each genotype had longer roots, though BAM-VR-312 had the longest roots overall. As the severity of the drought grew, the net photosynthetic rate (Pn) and stomatal conductance (Gs) dropped. In BAM-VR-312, a smaller decline in relative water content (RWC) was recorded, despite the fact that drought stress caused a significant fall in RWC. BAM-VR-312 had smaller accumulations of electrolyte leakage, hydrogen peroxide, phenol and malondialdehyde, although proline content was greater. A decrease in photosynthetic pigments was noted, though BAM-VR-312 had the least reduction. Antioxidant enzyme activity increased in BAM-VR-312, as evidenced by records of ascorbate peroxidase, catalase, guaiacol peroxidase, glutathione reductase and superoxide dismutase. Similarly, expression level of their respective genes was recorded highest in BAM-VR-312. Overall, the study clearly identified distinct genotype based on morpho-physiological, biochemical and molecular properties under drought stress and revealed that the genotype BAM-VR-312 had more efficient drought tolerance mechanisms than the other genotypes under the drought stress condition.