Global climate change enhances the effect of abiotic stress factors, which cause limited plant growth, yield losses, and reduced quality. Today, flooding has become an important stress factor restricting plant growth. Recently, researchers have worked out strategies that increase tolerance to flooding stress (Flo). This study aimed to examine the effects of Flo applied to melon cultivars on their agronomic and physio-biochemical properties. Commercially grown cultivars of melon, which is an important vegetable species with economic importance worldwide, included Kırkağaç type Sarı F1 (C1), Damla F1 (C2), Yucel F1 (C3), 1071 (candidate) (C4), Sürmeli F1 (C5), Westeros F1 (C6), Kırkagac 637 (C7), Kırkağaç 589 (C8), Super Soykan (C9), Kırkağaç local (C10), and Kyrgyzstan local (C11) which were the first treatment in this study. Another treatment was full irrigation (FI) and Flo. After 10 days of the application of flooding stress to plants during seedling growth, they were harvested, and some related measurements of their parameters were made. As a result of Flo application, all melon cultivars were adversely affected, as observed by decreases in values of plant fresh weight, plant dry weight, number of leaves, plant height, root fresh weight, root dry weight, and leaf area by approximately 30, 21, 24, 21, 28, 38 and 39%, respectively. Moreover, Flo negatively affected photosynthesis and pigment content, causing an increase of 47% in the malondialdehyde (MDA) content and 50% in the hydrogen peroxide (H2O2) content. On the other hand, significant increases were observed in proline and protein contents and antioxidant enzyme activities under stress. Based on the evaluated data, Kırkağaç 637, Kırkağaç 589, and Kyrgyzstan local cultivars that were the least affected by stress were identified as tolerant cultivars, while the most affected cultivars, Sarı F1 and Yücel F1, were found to be the sensitive cultivars.