Protein modulation is a process of changing protein structure which is either derived or deliberately induced. This leads to variation in protein activity during protein-protein interactions and can be utilized to understand disease mechanisms or to develop novel therapeutics. In this context, COX-2, iNOS and GST along with basic liver biochemistry were examined in experimentally injured rats and quercetin (QC) supplementation. Diethylnitrosamine (10 ml/kgbwt of 1%DEN) was used to generate liver injury in animals. Quercetin was administered at 60 mg/kgbwt daily in DEN-treated animals to investigate the effect. Hepatic AST/ALT/ALP/γGT, bilirubin, glycogen, LPO, CAT, SOD, GST, collagen levels, protein oxidation and nitrites were examined in all animals. Besides, histopathology and immunohistochemistry of COX-2 and iNOS was performed in tissue sections. Molecular docking of quercetin with human COX-2, iNOS and GST was performed by Autodock 4.2.6 software while drug likeliness and the properties of the ligand by SWISS-ADME and admetSAR and Molinspiration respectively. Our results demonstrate disturbed primary liver function concomitant with disconcert liver biochemistry and anatomy in DEN-treated animals (p < 0.05). Immunohistochemistry exhibited up-regulation of COX-2 and iNOS during liver injury. Molecular docking showed quercetin as acceptable drug as it passes Lipinski rule and shows binding with GST, iNOS, COX-2. In conclusion, COX-2, iNOS and GST appears to be the dynamic molecular targets of Quercetin action to restore tissue biochemistry and anatomy during experimental liver injury.