Background: Liver diseases such as nonalcoholic fatty liver disease (NAFLD) and drug-induced liver injury (DILI) are increasingly prevalent and are associated with oxidative stress, inflammation, and fibrosis. Conventional treatments are limited by single-target effects and side effects. Natural flavonoids such as quercetin and silibinin offer multitarget hepatoprotective properties, but their synergistic potential requires further molecular elucidation.

Methods: We employed a bioinformatics-based molecular docking approach to examine the individual and combined interactions of quercetin and silibinin with three hepatic targets: the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) complexes, transforming growth factor-β receptor II (TGF-βRII), and Cytochrome P450 3A4 (CYP3A4). Ligand structures were obtained from PubChem, and protein structures were obtained from the Protein Data Bank. Docking simulations were conducted via the Molegro Virtual Docker (MVD), with 50 runs per ligand. Binding energies, hydrogen bonds, interaction energy, and electrostatic interactions were analyzed.

Results: Quercetin and silibinin presented distinct but complementary binding patterns. Quercetin had the strongest affinity for Keap1/Nrf2 (−12.0 kcal/mol), whereas silibinin was more potent against CYP3A4 (−13.6 kcal/mol). Their combination enhanced binding across all the targets, especially TGF-βRII (−11.2 kcal/mol), indicating synergy (*p < 0.01). Additionally, quercetin formed stronger interaction energy with Keap1 (−34.6 kcal/mol), whereas silibinin contributed greater hydrogen bond energy with TGF-βRII (−10.5 kcal/mol). Codocking improved electrostatic interactions across all the targets, notably for TGF-βRII (−0.7 kcal/mol) and CYP3A4 (−0.6 kcal/mol), supporting structural complementarity and cooperative binding.

Conclusion: Quercetin and silibinin demonstrate synergistic molecular interactions with key liver disease targets through diverse binding forces. Their combined use enhances binding affinity, stability, and interaction diversity, validating their potential as a dual phytotherapeutic strategy. These findings encourage further experimental validation and formulation development.