Watermelon (Citrullus lanatus) is an economically important cucurbitaceous crop worldwide. The productivity of watermelon is affected by both biotic and abiotic stresses. Flooding has significant impacts on the growth of watermelons by causing oxygen deficiency and a loss of agricultural productivity. Currently, we used the triploid and diploid watermelon Zhengzhou No.3 to study the dynamics of metabolites in response to flooding stress. Quantification of metabolites was performed by UPLC-ESI-MS/MS at different time intervals i.e., 0, 3, 5 and 7 days under flooding stress. We observed that the activities of oxidants were higher in the diploid watermelon, whereas the higher antioxidant activities in the triploid watermelon makes them more resistant to the flooding stress. We also observed that the root activity and the chlorophyll in the triploid watermelon plants were higher as compared to the diploid watermelon plants. Co-expression network analysis leads to the identification of twenty-four hub metabolites that might be the key metabolites linked to flooding tolerance. Resolving the underlying mechanisms for flooding tolerance and identification of key molecules serving as indicators for breeding criteria are necessary for developing flooding-resistant varieties.