Purpose <p>Enhancing oral bioavailability remains a key focus in modern medicine. Among various bioenhancers, flavonoid polyphenols show significant promise by inhibiting efflux proteins like P-glycoprotein (P-gp), thereby improving intestinal permeability and systemic drug absorption. This study evaluates the P-gp binding affinity of two flavonoids, Naringin (NRG) and Quercetin (QCT), to explore their potential in enhancing the permeability of the P-gp substrate, Curcumin (CUR).</p> Methods <p>P-gp binding affinities of NRG and QCT were evaluated in silico to identify the optimal co-former for CUR in co-amorphous mixture (CAM). Differential Scanning Calorimetry (DSC) was used to preliminarily select the suitable P-gp inhibitor. The chosen co-former was then evaluated for ex vivo permeability studies.</p> Results <p>NRG demonstrated a more favorable MM-GBSA binding energy to P-gp (-39.76&#xa0;kcal/mol vs. -35.16&#xa0;kcal/mol for QCT), suggesting a stronger and more stable interaction overall. Additionally, DSC analysis unveiled the conversion of CUR from a crystalline to an amorphous form when co-formulated with NRG, likely accredited to the glass-forming ability of NRG. In contrast, CAM of CUR with QCT did not induce transformation of crystalline CUR into its amorphous form which could attributed to the formation of poor glass structures within the CAM. To further validate the P-gp inhibition potential of NRG, <i>ex-vivo</i> permeability studies were carried out and the CAM of CUR and NRG in molar ratio 1:2 demonstrated a maximum of 19-fold increase than CUR (P &lt; 0.05). CAM (1:1) and physical mixture displayed 3.8-and 2-folds increase in permeability than CUR, respectively (P &lt; 0.05).</p> Conclusion <p>These study findings are indicative of potential advantage of NRG as a co-former, promising improved oral bioavailability of CUR.</p>