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.