The development of varieties tolerant to water stress holds a prominent position among these strategies. In this study to evaluate 20 melon inbred genotypes, 4 commercial cultivars for water stress tolerance in terms of yield, physiological and biochemical properties, and stress tolerance indices under full irrigation (I100) and 50% water stress (I50) conditions for two years. The results showed a decrease in yield, leaf area, and relative water content but significant increases in membrane permeability, malondialdehyde, hydrogen peroxide, proline, and protein contents, as well as antioxidant enzyme activity under water stress. Principal component analysis (PCA) found the mean productivity, stress tolerance index, geometric mean productivity, and harmonic mean as important stress tolerance indices that could evaluate the performance of genotypes for drought tolerance. Although hybrid varieties G3 and G4 and some melon inbred lines (G6, G22, and G58) stood out as the genotypes tolerant to water stress, the inbred lines G11, G14, G33, G35, G37, G61, and G63 were identified as drought-sensitive genotypes. Data obtained in this study allow us to gain new insights into the mechanisms of significant yield loss and changes in physiological and biochemical characteristics of melons grown under water deficit in semiarid areas.