The low bioavailability of polyphenols, such as resveratrol (RES), is typically caused by the poor solubility and first-pass effect. To improve bioavailability and reduce adverse effects, an oral reversible UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) dual-target-mild-inhibition strategy was designed, and a proof-of-concept was studied. This R-Q@P-D nanoparticle for the codelivery of RES and quercetin (QUE) was constructed using pea protein isolate and dipotassium glycyrrhizinate (DG) as nanocarriers. These nanoparticle ingredients were all plant extracts approved by the FDA, and the fabrication process was a simple but novel pH-ultrasonic-shifting method in water conditions. R-Q@P-D exhibited high encapsulation efficiency of RES (97.25 ± 1.13 %) and QUE (94.21 ± 0.62 %), with a uniform nanosize (147.73 ± 1.85 nm). Characterizations implied that RES and QUE could be successfully encapsulated in nanoparticles in amorphous states, and the self-assembly binding between them was non-covalent bonds. Moreover, the in-silicon simulation and experimental results verified interactions between RES and DG, while there was no interaction between QUE and DG. In vivo evaluations showed that R-Q@P-D increased the bioavailability of RES by mildly and reversibly inhibiting intestinal UGTs and SULTs, but without inhibiting hepatic UGTs and SULTs. Moreover, molecular simulations showed that QUE and RES are competitively bound to SULTs but not UGTs. R-Q@P-D had significant therapeutic efficacy and excellent safety performance for its oral application. The tremendous safety and simple fabrication benefited the clinical translation. Together, R-Q@P-D based on reversible UGTs and SULTs dual-target-mild-inhibition strategy might be a promising nano-platform for improving the bioavailability and efficacy of hydrophobic polyphenols.