A growing number of nanomaterials are being broadly used in food-related fields as well as therapeutics. Oral exposure to these widespread nanomaterials is inevitable, with the intestine being a major target organ. Upon encountering the intestine, these nanoparticles can cross the intestinal barrier, either bypassing cells or via endocytosis pathways to enter the adjacent mesentery. The intricate structure of the mesentery and its entanglement with the abdominal digestive organs determine the final fate of nanomaterials in the human body. Importantly, mesentery-governed dynamic processes determine the distribution and subsequent biological effects of nanomaterials that cross the intestine, thus there is a need to understand how nanomaterials interact with the mesentery. This review presents the recent progress in understanding the mesenteric structure and function and highlights the importance of the mesentery in health and disease, with a focus on providing new insights and research directions around the biological effects of nanomaterials on the mesentery. A thorough comprehension of the interactions between nanomaterials and the mesentery will facilitate the design of safer nanomaterial-containing products and the development of more effective nanomedicines to combat intestinal disorders.