Drought, which has emerged as one of the major effects of global climate change, has led to an increasing demand for water resources. For this reason, it is necessary to utilize the water available in agriculture in the most efficient way. Therefore, breeding with drought-tolerant species and cultivars is an important approach in terms of water conservation. In general, melon cultivation is performed in open field conditions and especially in regions with semi-arid climates. In these regions, accessing irrigation water is quite difficult. Therefore, the present study aimed to determine agronomic, physiological, and biochemical changes as well as tolerant genotypes of inbred line melon breeding materials under full irrigation (I100) and moderate water stress (I50) conditions. To accomplish this, 80 Altınbaş (Kırkağaç type) selected melon genotypes, two standard cultivars (G1-Super Soykan, G2-Kırkağaç 637), and two hybrid cultivars (G3-Sürmeli F1, G4-Westeros F1) were used as plant material. According to the study, the applied 50 % water deficit exhibited a negative impact on agronomic characteristics. On the other hand, water stress reduced the efficiency of photosynthesis in melon genotypes and increased the compounds that damage plant cells, such as malondialdehyde (MDA) and hydrogen peroxide (H2O2). As a result of principal component analysis (PCA), genotypes 5, 6, 11, 12, 14, 15, 22, 33, 35, 37, 40, 57, 58, 61, 62, 63, 64, 70, 79, and 82 were determined as drought-tolerant genotypes. Genotype 14, on the other hand, which has a higher water use efficiency (WUE) in comparison to commercial cultivars under both full and deficit irrigation, has proven to be crucial for water conservation in arid and semi-arid regions.