Fluoride (F) has been employed worldwide to control dental caries. More recently, it has been suggested that the consumption of low doses of F in the drinking water may reduce blood glucose levels, introducing a new perspective for the use of F for the management of blood glucose. However, the exact mechanism by which F affects blood glucose levels remains largely unexplored. Given that the small gut plays a pivotal role in glucose homeostasis, the aim of this present study was to investigate the proteomic changes induced by low doses of F in the ileum of female non-obese-diabetic (NOD) mice. Forty-two female NOD mice were divided into two groups based on the F concentration in their for 14 weeks: 0 (control) or 10 mg/L. At the end of the experimental period, the ileum was collected for proteomic and Western Blotting analyses. Proteomic analysis indicated an increase in isoforms of actin, gastrotropin (confirmed by Western Blotting), several H2B histones and enzymes involved in antioxidant processes, as well as a decrease in enzymes essential for energy metabolism. In summary, our data indicates an adaptive response of the organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism typically induced by F, therefore highlighting the safety of controlled fluoridation in water supplies.