Simple Summary Pumpkins (Cucurbita moschata), valued for their nutritional, medicinal, and economic contributions, are threatened by root-knot nematodes, notably Meloidogyne incognita. This research explores the impact of M. incognita on the growth and comprehensive physiological responses of pumpkins. The findings reveal that infection leads to significant growth impairment, as indicated by reduced plant height and biomass along with the development of nematode-induced galls. In addition, there is an observable oxidative stress response characterized by elevated levels of hydrogen peroxide and an increase in antioxidant defense mechanisms such as crucial antioxidative enzymes (superoxide dismutase, glutathione reductase, and catalase) and the accumulation of glutathione. These responses demonstrate a dynamic interplay between the plant and the nematode, where pumpkins mobilize robust antioxidant defenses to counteract the stress induced by nematode infection. Despite these defense mechanisms, pumpkin's ability to combat M. incognita raises concerns about the agricultural production challenges posed by this pest in Cucurbita crops. The insights gained from this study improve our understanding of plant-nematode interactions, paving the way for strategies aimed at increasing resistance against these pests, thus promoting sustainable agricultural practices. Pumpkins (Cucurbita moschata), valued for their nutritional, medicinal, and economic significance, face threats from Meloidogyne incognita, a critical plant-parasitic nematode. This study extensively examines the impact of M. incognita on the growth, physiological, and biochemical responses of C. moschata. We demonstrate that M. incognita infection leads to significant growth impairment in C. moschata, evidenced by reduced plant height and biomass, along with the significant development of nematode-induced galls. Concurrently, a pronounced oxidative stress response was observed, characterized by elevated levels of hydrogen peroxide and a significant increase in antioxidant defense mechanisms, including the upregulation of key antioxidative enzymes (superoxide dismutase, glutathione reductase, catalase, and peroxidase) and the accumulation of glutathione. These responses highlight a dynamic interaction between the plant and the nematode, wherein C. moschata activates a robust antioxidant defense to mitigate the oxidative stress induced by nematode infection. Despite these defenses, the persistence of growth impairment underscores the challenge posed by M. incognita to the agricultural production of C. moschata. Our findings contribute to the understanding of plant-nematode interactions, paving the way for the development of strategies aimed at enhancing resistance in Cucurbitaceae crops against nematode pests, thus supporting sustainable agricultural practices.