Molybdenum disulfide nanoparticles (MoS2NPs) have attracted considerable attention in the fields of environmental protection and agricultural production. Understanding the potential crop risk (especially in edible parts) incurred by MoS2NPs and the corresponding plant defense against toxicity is a prerequisite for assessing human dietary safety and improving the safe‐by design of such NPs; however, relevant information remains largely unknown. This study examines the toxicity of MoS2NPs to edible vegetable crops of pepper and their corresponding defense mechanisms. Our findings revealed that exposure to MoS2NPs triggered the defense in pepper via reducing transpiration rates in leaves by 36.5%–54.8% and via increasing catalase activity, mineral elements, and gibberellic acid in fruit by 10.7%–32.4%, 0.2%–92.8%, and 28.0%–72.4%, respectively. The defensive response to MoS2NPs stress was also reflected in the elevated amino acid metabolism (e.g., arginine and proline metabolism in leaves, and alanine, aspartate, and glutamate metabolism in fruits), and in the regulation of the oxidation–reduction process proteins in fruits (e.g., increased acyl‐coenzyme A oxidase and cytochrome P450, decreased NADH–ubiquinone oxidoreductase chain and cytokinin dehydrogenase). However, oxidative stress in pepper fruits (e.g., increased H2O2 and malondialdehyde, ultrastructural damage, reduced biomass) was still induced by MoS2NPs, suggesting an unbalance between defense systems and abiotic stress. This study provides valuable insights into the impacts of MoS2NPs on edible parts of crops and helps to assess their ecological risk.