Nile tilapia (Oreochromis niloticus) is the world's most widely cultured fish species. Therefore, its nutritional physiology is of great interest from an aquaculture perspective. Studies conducted on several fish species, including tilapia, demonstrated the beneficial effects of dietary salt supplementation on growth; however, the mechanism behind these beneficial effects is still not fully understood. The fish intestine is a complex system, with functions, such as nutrient absorption, ion equilibrium and acid-base balance that are tightly linked and dependent on each other's activities and products. Ions are the driving force in the absorption of feed components through pumps, transporters and protein channels. In this study, we examined the impact of 5% increase in dietary NaCl on protein, lipid, ash and dry matter digestibility, as well as on the expression of intestinal peptide transporters (PepTs) and ion pumps (Na+/K+-ATPase, V-H+-ATPase, N+/H+-Exchanger) in Nile tilapia. In addition, effects on the gut microbiome were evaluated. Our results show that dietary salt supplementation significantly increased digestibility of all measured nutritional components, peptide transporters expression and ion pumps activity. Moreover, changes in the gut microbial diversity were observed, and were associated with lipid digestibility and Na+/K+-ATPase expression.