Humans are frequently exposed to the residues of various neonicotinoids, highlighting the need to understand human exposure through oral ingestion of contaminated foods. In this study, the effects of different food matrices (tomato, cucumber, and carrot) and their interaction with dietary component additives, including proteins and dietary fiber, was investigated. The results showed that the presence of a food matrix had a significant effect on the bioaccessibility of neonicotinoids (imidacloprid, thiamethoxam, acetamiprid, and thiacloprid) in both the gastric and intestinal environments. Neonicotinoids in tomato presented relatively low bioaccessibility, indicating that the daily intake of the tomato can be regarded as being relatively safer. Moreover, the addition of protein or dietary fiber to fruit and vegetables had a marked influence on neonicotinoid bioaccessibility and the effects varied between the different matrices. In particular, the addition of 2.0% dietary fiber significantly reduced the bioaccessibility (18.38-67.91%). Therefore, we recommend that consuming an increased intake of dietary fiber could improve the safety of fruit and vegetables in daily life. The present results can support the identification of suitable food intake conditions for the significant reduction of pesticide residue levels.