The oral route of administration continues to be the preferred and most convenient method for drug delivery among both patients and healthcare professionals. This preference is based not only on its user-friendliness but also on the practicality it provides regarding formulation flexibility and dosage adjustability. Nevertheless, the effectiveness of oral drug delivery is significantly influenced by the ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of the drug. Among these characteristics, permeability is a key factor affecting oral bioavailability, making the exploration of permeability enhancers a vital research focus to boost oral absorption. Recent investigations have highlighted sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) as a promising permeability enhancer, demonstrating its potential to increase the absorption rates of various substances. Despite its proven effectiveness, the precise mechanisms by which SNAC promotes this enhancement are not yet fully understood. Furthermore, the specific dosage of SNAC required to improve drug absorption remains unclear. This study aims to examine the dose-dependent effects of SNAC on the model compound cyanocobalamin (Vitamin B12) in rats. The in vivo findings were integrated with modeling and simulation to determine the critical concentration of SNAC and the minimum molar ratio, and the overall enhancement effect at various SNAC concentrations for cyanocobalamin needed to achieve permeation enhancement. This knowledge could assist formulators in more effectively incorporating SNAC into formulations for enhanced therapeutic outcomes.