The intestinal mucosal barrier (IMB) is one of the important barriers to prevent harmful substances and pathogens from entering the body environment and to maintain intestinal homeostasis. The dysfunction of the IMB is associated with intestinal diseases and disorders. Nanomaterials have been widely used in medicine and as drug carriers due to their large specific surface area, strong adsorbability, and good biocompatibility. In this review, we comprehensively discuss the impact of typical nanomaterials on the IMB and summarize the treatment of intestinal diseases by using nanomaterials. The effects of nanomaterials on the IMB are mainly influenced by factors such as the dosage, size, morphology, and surface functional groups of nanomaterials. There is huge potential and a broad prospect for the application of nanomaterials in regulating the IMB for achieving an optimal therapeutic effect for antibiotics, oral vaccines, drug carriers, and so on.